WO2024163494A1

WO2024163494A1 - Methods and compositions for treating non-small cell lung cancer and triple-negative breast cancer

Info

Publication number: WO2024163494A1
Application number: PCT/US2024/013579
Authority: WO
Inventors: Vladan ANTIC; Stephen CHUI; Hans-Joachim HELMS; Lucas MALARD VELLOSO; Aruna MANI; David Merritt; Stefanie MORRIS; Merlind Muecke
Original assignee: F Hoffmann La Roche AG; Genentech Inc; Hoffmann La Roche Inc
Current assignee: F Hoffmann La Roche AG; Genentech Inc; Hoffmann La Roche Inc
Priority date: 2023-01-31
Filing date: 2024-01-30
Publication date: 2024-08-08
Anticipated expiration: 2025-07-31
Also published as: TW202436339A; WO2024163494A8

Abstract

This invention relates to methods and compositions for use in treating a non-small cell lung cancer (NSCLC) in a subject by administering to the subject a bispecific antibody targeting programmed cell death protein 1 (PD-1 ) and lymphocyte activation gene-3 (LAGS) (PD1 -LAG3) and (a) carboplatin and paclitaxel or (b) carboplatin and pemetrexed. This invention also relates to methods and compositions for use in treating a triple-negative breast cancer (TNBC) in a subject by administering to the subject PD1 -LAG3 and nab-paclitaxel.

Description

METHODS AND COMPOSITIONS FOR TREATING NON-SMALL CELL LUNG CANCER AND TRIPLE-NEGATIVE BREAST CANCER

SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on January 30, 2024, is named 51177-050W02_Sequence_Listing_1_30_24 and is 37,424 bytes in size.

FIELD OF THE INVENTION

This invention relates to methods and compositions for use in treating a non-small cell lung cancer (NSCLC) in a subject by administering to the subject a bispecific antibody targeting programmed cell death protein 1 (PD-1 ) and lymphocyte activation gene-3 (LAG3) (PD1 -LAG3) and (a) carboplatin and paclitaxel or (b) carboplatin and pemetrexed. This invention also relates to methods and compositions for use in treating a triple-negative breast cancer (TNBC) in a subject by administering to the subject PD1 -LAG3 and nab-paclitaxel.

BACKGROUND OF THE INVENTION

Lung cancer remains the leading cause of cancer deaths worldwide. NSCLC accounts for approximately 85% of all cases of lung cancer. NSCLC can be divided into two subcategories: squamous (SQ) and non-squamous (NSQ). SQ cell histology accounts for approximately 25% of NSCLCs. NSQ NSCLC includes several histologic subtypes, the most common of which is adenocarcinoma, which accounts for more than half of all NSCLC cases. The remaining cases of NSCLC are represented by other NSQ NSCLC histologies, including large cell carcinoma, neuroendocrine tumors, sarcomatoid carcinoma, and those with poorly differentiated histology.

Standard-of-care treatment for patients with advanced NSQ NSCLC in the first-line setting is largely driven by results of molecular profiling. The preferred first-line treatment for patients with tumors harboring an oncogenic driver mutation utilizes an approved targeted therapy, if available. For patients whose tumors lack a targetable oncogenic aberration, current standard-of-care treatment regimens in the first-line setting typically consist of an immune checkpoint inhibitor (CPI), including programmed death-1 (PD-1 )- and programmed death ligand 1 (PD-L1 )-blocking antibodies, with or without platinum-based doublet chemotherapy and bevacizumab. The current standard of care for newly diagnosed patients with advanced-stage SQ NSCLC includes paclitaxel or gemcitabine in combination with a platinum agent.

Despite significant advances with combination immunotherapy and the approval of immune CPI agents in combination with chemotherapy as first-line therapy for patients with advanced NSCLC, the majority of patients with advanced NSCLC progress during treatment and ultimately experience disease progression and succumb to this disease. Therefore, a high unmet medical need persists for patients with advanced NSCLC.

Breast cancer is the most frequently diagnosed cancer among women, and the leading cause of cancer-related deaths in women worldwide. TNBC accounts for 12%-20% of newly diagnosed breast cancer cases. TNBC is characterized immunohistologically by the lack of expression of hormonal estrogen receptor (ER) and progesterone receptor (PgR), and lack of overexpression and/or amplification of the human epidermal growth factor receptor 2 (HER2)/neuraminidase (NEU) gene. Compared with other breast cancer subtypes, TNBC tumors are generally larger in size, more poorly differentiated, have more extensive lymph node involvement at diagnosis, and exhibit an invasive phenotype. Patients with TNBC have a higher risk of both local and distant recurrence, and metastases are more likely to occur in visceral organs and the brain, rather than bone, when compared with patients with other breast cancers. Patients with metastatic TNBC have relatively poorer outcomes (shorter duration of progression-free survival (PFS) and overall survival (OS)) compared with patients with other breast cancer subtypes. In the early-disease setting, this is manifested in a shorter time to recurrence and shorter OS compared with patients with other breast cancers. Breast cancer is generally considered incurable once it has metastasized.

The treatment approach for this disease in the first-line (1 L) setting is chemotherapy, in combination with an anti-programmed death-1 (PD-1 )/PD-L1 inhibitor for patients with PD-L1 -positive TNBC, where approved and accessible (e.g., atezolizumab, pembrolizumab). OS in the 1 L metastatic setting remains modest at less than 3 years. Therefore, there remains an urgency to improve upon chemotherapy in combination with PD-1/PD-L1 -targeting agents in 1 L PD-L1 -positive advanced TNBC. Combinations targeting novel immune checkpoints are attractive because they aim to take advantage of distinct mechanisms that could improve the success of immunotherapy in TNBC and potentially expand the proportion of patients whose tumors respond to immunotherapy.

SUMMARY OF THE INVENTION

In one aspect, the disclosure provides a method for treating a subject having a non-squamous non-small cell lung cancer (NSCLC), the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of (a) a bispecific antibody targeting PD-1 and LAG3 comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3; (b) pemetrexed; and (c) carboplatin.

In some aspects, the method comprises administering to the subject the bispecific antibody at a fixed dose of 600 mg every three weeks.

In some aspects, the method comprises administering to the subject the pemetrexed at a dose of 500 mg/m² every three weeks.

In some aspects, the method comprises administering to the subject the carboplatin at a targeted area under the concentration-time curve (AUC) of 5 mg/mL • min every three weeks.

In some aspects, the length of each of the one or more dosing cycles is 21 days, and the method comprises administering to the subject the bispecific antibody, the pemetrexed, and the carboplatin on Day 1 of each of the one or more dosing cycles.

In some aspects, the method comprises (a) administering to the subject the bispecific antibody first, the pemetrexed second, and the carboplatin third, or (b) administering to the subject the pemetrexed first, the carboplatin second, and the bispecific antibody third.

In some aspects, the method comprises administering to the subject the bispecific antibody, the pemetrexed, and the carboplatin intravenously. In some aspects, (a) the bispecific antibody is administered over 60 (± 15) minutes in a first dosing cycle; (b) the method comprises one or more additional dosing cycles, and the bispecific antibody is administered over 30 (± 10) minutes in the one or more additional dosing cycles; (c) the pemetrexed is administered over 10 minutes; and/or (d) the carboplatin is administered over 30-60 minutes.

In some aspects, the dosing regimen comprises four dosing cycles.

In some aspects, the dosing regimen further comprises one or more additional dosing cycles of (a) the bispecific antibody and (b) pemetrexed.

In some aspects, the dosing regimen comprises at least 5 or at least 10 additional dosing cycles of (a) the bispecific antibody and (b) pemetrexed.

In another aspect, the disclosure provides a method for treating a subject having a squamous NSCLC, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of (a) a bispecific antibody targeting PD-1 and LAG3 comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3; (b) paclitaxel; and (c) carboplatin.

In some aspects, the method comprises administering to the subject the paclitaxel at a dose of 200 mg/m² every three weeks.

In some aspects, the method comprises administering to the subject the carboplatin at a targeted AUC of 5 mg/mL • min every three weeks.

In some aspects, the length of each of the one or more dosing cycles is 21 days, and the method comprises administering to the subject the bispecific antibody, the paclitaxel, and the carboplatin on Day 1 of each of the one or more dosing cycles.

In some aspects, the method comprises (a) administering to the subject the bispecific antibody first, the paclitaxel second, and the carboplatin third, or (b) administering to the subject the paclitaxel first, the carboplatin second, and the bispecific antibody third.

In some aspects, the method comprises administering to the subject the bispecific antibody, the paclitaxel, and the carboplatin intravenously.

In some aspects, (a) the bispecific antibody is administered over 60 (± 15) minutes in a first dosing cycle; (b) the method comprises one or more additional dosing cycles, and the bispecific antibody is administered over 30 (± 10) minutes in the one or more additional dosing cycles; (c) the paclitaxel is administered over 3 hours; and/or (d) the carboplatin is administered over 30-60 minutes.

In some aspects, the dosing regimen comprises four dosing cycles.

In some aspects, the dosing regimen further comprises one or more additional dosing cycles of the bispecific antibody.

In some aspects, the dosing regimen comprises at least 5 or at least 10 additional dosing cycles of the bispecific antibody.

In some aspects, the subject is premedicated with an oral or IV steroid and antihistamines prior to administration of the paclitaxel.

In some aspects, the NSCLC is (a) a Stage IIIB/IIIC NSCLC; or (b) a Stage IV NSCLC.

In some aspects, the subject has not received prior systemic treatment for metastatic NSCLC. In some aspects, the subject has not previously been treated with an immune checkpoint blockade therapy.

In some aspects, the subject has not previously been treated with an anti-cytotoxic T lymphocyte-associated protein 4 (CTLA4) agent, an anti-T cell immunoreceptor with Ig and tyrosinebased inhibition motif domains (TIGIT) agent, an anti-PD-1 therapeutic antibody, an anti-PD-L1 therapeutic antibody, or an anti-LAG3 agent.

In some aspects, the subject has not previously been treated with a CD137 agonist.

In some aspects, the subject does not have any symptomatic, untreated, or actively progressing central nervous system (CNS) metastases.

In some aspects, the subject does not have a known mutation in the epidermal growth factor receptor (EGFR) gene or an anaplastic lymphoma kinase (ALK) fusion oncogene.

In some aspects, the subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 .

In some aspects, a tumor sample from the NSCLC of the subject has a PD-L1 tumor proportion score (TPS) or a PD-L1 expression level on tumor cells (TCs) of <1%.

In some aspects, a tumor sample from the NSCLC of the subject has a PD-L1 TPS or a PD-L1 expression level on TCs of between 1% and 49%.

In some aspects, a tumor sample from the NSCLC of the subject has a PD-L1 TPS or a PD-L1 expression level on TCs of >50%.

In some aspects, the method results in an increase in progression-free survival (PFS) as compared to a reference PFS. In some aspects, the reference PFS is a PFS of a population of subjects who have received a control therapy.

In some aspects, the method results in an increase in objective response rate (ORR) in a population of subjects treated according to the method as compared to a reference ORR. In some aspects, the reference ORR is an ORR of a population of subjects who have received a control therapy.

In some aspects, the method results in an increase in overall survival (OS) as compared to a reference OS. In some aspects, the reference OS is an OS of a population of subjects who have received a control therapy.

In some aspects, the method results in an increase in duration of response (DOR) as compared to a reference DOR. In some aspects, the reference DOR is a DOR of a population of subjects who have received a control therapy.

In some aspects, (a) the subject has a non-squamous NSCLC, and the control therapy comprises pembrolizumab, pemetrexed, and carboplatin and does not comprise the bispecific antibody; or (b) the subject has a squamous NSCLC, and the control therapy comprises pembrolizumab, paclitaxel, and carboplatin and does not comprise the bispecific antibody.

In some aspects, the bispecific antibody targeting PD-1 and LAG3 comprises a first antigenbinding domain that specifically binds to PD-1 comprising a heavy chain variable (VH) domain comprising

(i) a hypervariable region H1 (HVR-H1 ) sequence comprising the amino acid sequence of SEQ ID NO: 1 ,

(ii) an HVR-H2 sequence comprising the amino acid sequence GGR, and (iii) an HVR-H3 sequence comprising an amino acid sequence of SEQ ID NO: 2; and a light chain variable (VL) domain comprising (i) an HVR-L1 sequence comprising the amino acid sequence of SEQ ID NO: 3; (ii) an HVR-L2 sequence comprising the amino acid sequence RSS, and (iii) an HVR-L3 sequence comprising the amino acid sequence of SEQ ID NO: 4.

In some aspects, the bispecific antibody targeting PD-1 and LAG3 comprises a Fc domain that is an IgG. In some aspects, the IgG Fc domain is an IgG 1 Fc domain or an lgG4 Fc domain.

In some aspects, the Fc domain comprises one or more amino acid substitutions that reduce binding to an Fc receptor. In some aspects, the Fc receptor is an Fey receptor.

In some aspects, the bispecific antibody targeting PD-1 and LAG3 comprises a second antigenbinding domain that specifically binds to LAG3 comprising a VH domain comprising (i) an HVR-H1 sequence comprising the amino acid sequence of SEQ ID NO: 7, (ii) an HVR-H2 sequence comprising the amino acid sequence of SEQ ID NO: 8, and (iii) an HVR-H3 sequence comprising an amino acid sequence of SEQ ID NO: 9; and a VL domain comprising (i) an HVR-L1 sequence comprising the amino acid sequence of SEQ ID NO: 10, (ii) an HVR-L2 sequence comprising the amino acid sequence of SEQ ID NO: 11 , and (iii) an HVR-L3 sequence comprising the amino acid sequence of SEQ ID NO: 12.

In some aspects, the first antigen-binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 5 and a VL domain comprising the amino acid sequence of SEQ ID NO: 6, and the second antigen-binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 13 and a VL domain comprising the amino acid sequence of SEQ ID NO: 14.

In some aspects, the bispecific antibody targeting PD-1 and LAG3 comprises (a) an Fc domain of human IgG 1 subclass with the amino acid mutations L234A, L235A, and P329G (numbering according to Kabat EU index); and/or (b) an Fc domain comprising a modification promoting the association of the first and second subunit of the Fc domain.

In some aspects, the first subunit of the Fc domain comprises the amino acid substitutions S354C and T366W (numbering according to Kabat EU index) and the second subunit of the Fc domain comprises the amino acid substitutions Y349C, T366S, and Y407V (numbering according to Kabat EU index).

In some aspects, the bispecific antibody targeting PD-1 and LAG3 comprises a first Fab fragment comprising said first antigen binding domain specifically binding to PD1 comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 5 and a VL domain comprising the amino acid sequence of SEQ ID NO: 6, and a second Fab fragment comprising the second antigen binding domain specifically binding to LAG3 comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 13 and a VL domain comprising the amino acid sequence of SEQ ID NO: 14, and an Fc domain of human IgG 1 subclass with the amino acid mutations L234A, L235A, and P329G (numbering according to Kabat EU index).

In some aspects, in one of the Fab fragments of the bispecific antibody targeting PD-1 and LAG3 the variable domains VL and VH are replaced by each other so that the VH domain is part of the light chain and the VL domain is part of the heavy chain.

In some aspects, in the first Fab fragment the variable domains VL and VH are replaced by each other.

In some aspects, in the constant domain CL of one of the Fab fragments the amino acid at position 124 is substituted independently by lysine (K), arginine (R), or histidine (H) (numbering according to Kabat EU Index), and in the constant domain CH1 the amino acids at positions 147 and 213 are substituted independently by glutamic acid (E) or aspartic acid (D) (numbering according to Kabat EU index).

In some aspects, in the constant domain CL of the second Fab fragment the amino acid at position 124 is substituted independently by lysine (K), arginine (R), or histidine (H) (numbering according to Kabat EU Index), and in the constant domain CH1 the amino acids at positions 147 and 213 are substituted independently by glutamic acid (E) or aspartic acid (D) (numbering according to Kabat EU index).

In some aspects, the bispecific antibody comprises a first heavy chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 15, a first light chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 16, a second heavy chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 17, and a second light chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 18.

In some aspects, the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 15, a first light chain comprising the amino acid sequence of SEQ ID NO: 16, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 17, and a second light chain comprising the amino acid sequence of SEQ ID NO: 18.

In another aspect, the disclosure provides a method for treating a subject having a non- squamous Stage IIIB/IIIC NSCLC or a Stage IV NSCLC, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of (a) a bispecific antibody targeting PD- 1 and LAG3 comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, wherein the method comprises administering to the subject the bispecific antibody at a fixed dose of 600 mg every three weeks, and wherein the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 15, a first light chain comprising the amino acid sequence of SEQ ID NO: 16, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 17, and a second light chain comprising the amino acid sequence of SEQ ID NO: 18; (b) pemetrexed, wherein the method comprises administering to the subject the pemetrexed at a dose of 500 mg/m² every three weeks; and (c) carboplatin, wherein the method comprises administering to the subject the carboplatin at a targeted area under the concentration-time curve (AUC) of 5 mg/mL • min every three weeks.

In another aspect, the disclosure provides a method for treating a subject having a squamous Stage IIIB/IIIC NSCLC or a Stage IV NSCLC, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of (a) a bispecific antibody targeting PD-1 and LAG3 comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigenbinding domain that specifically binds to LAG3, wherein the method comprises administering to the subject the bispecific antibody at a fixed dose of 600 mg every three weeks, and wherein the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 15, a first light chain comprising the amino acid sequence of SEQ ID NO: 16, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 17, and a second light chain comprising the amino acid sequence of SEQ ID NO: 18; (b) paclitaxel, wherein the method comprises administering to the subject the paclitaxel at a dose of 200 mg/m² every three weeks; and (c) carboplatin, wherein the method comprises administering to the subject the carboplatin at a targeted AUC of 5 mg/mL • min every three weeks.

In another aspect, the disclosure provides a bispecific antibody targeting PD-1 and LAG3 for use in a method of treating a subject having a non-squamous non-small cell lung cancer (NSCLC), wherein the method comprises a dosing regimen comprising a bispecific antibody targeting PD-1 and LAG3, pemetrexed, and carboplatin, wherein the bispecific antibody comprises a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, and wherein the dosing regimen comprises administering to the subject one or more dosing cycles of (a) the bispecific antibody; (b) pemetrexed; and (c) carboplatin.

In some aspects, the method comprises administering to the subject the bispecific antibody, the pemetrexed, and the carboplatin intravenously.

In some aspects, (a) the bispecific antibody is to be administered over 60 (± 15) minutes in a first dosing cycle; (b) the method comprises one or more additional dosing cycles, and the bispecific antibody is to be administered over 30 (± 10) minutes in the one or more additional dosing cycles; (c) the pemetrexed is to be administered over 10 minutes; and/or (d) the carboplatin is to be administered over 30-60 minutes.

In some aspects, the dosing regimen comprises four dosing cycles.

In another aspect, the disclosure provides a bispecific antibody targeting PD-1 and LAG3 for use in a method of treating a subject having a squamous NSCLC, wherein the method comprises a dosing regimen comprising a bispecific antibody targeting PD-1 and LAG3, paclitaxel, and carboplatin, wherein the bispecific antibody comprises a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, and wherein the dosing regimen comprises administering to the subject one or more dosing cycles of (a) the bispecific antibody; (b) paclitaxel; and (c) carboplatin. In some aspects, the method comprises administering to the subject the bispecific antibody at a fixed dose of 600 mg every three weeks.

In some aspects, (a) the bispecific antibody is to be administered over 60 (± 15) minutes in a first dosing cycle; (b) the method comprises one or more additional dosing cycles, and the bispecific antibody is to be administered over 30 (± 10) minutes in the one or more additional dosing cycles; (c) the paclitaxel is to be administered over 3 hours; and/or (d) the carboplatin is to be administered over 30-60 minutes.

In some aspects, the dosing regimen comprises four dosing cycles.

In some aspects, the subject is to be premedicated with an oral or IV steroid and antihistamines prior to administration of the paclitaxel.

In some aspects, the subject has not received prior systemic treatment for metastatic NSCLC.

In some aspects, the subject has not previously been treated with an immune checkpoint blockade therapy.

In some aspects, the subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 . In some aspects, a tumor sample from the NSCLC of the subject has a PD-L1 tumor proportion score (TPS) or a PD-L1 expression level on tumor cells (TCs) of <1%.

In some aspects, the bispecific antibody targeting PD-1 and LAG3 comprises a second antigenbinding domain that specifically binds to LAG3 comprising a VH domain comprising (i) an HVR-H1 sequence comprising the amino acid sequence of SEQ ID NO: 7, (ii) an HVR-H2 sequence comprising the amino acid sequence of SEQ ID NO: 8, and (iii) an HVR-H3 sequence comprising an amino acid sequence of SEQ ID NO: 9; and a VL domain comprising (i) an HVR-L1 sequence comprising the amino acid sequence of SEQ ID NO: 10, (ii) an HVR-L2 sequence comprising the amino acid sequence of SEQ ID NO: 11 , and (iii) an HVR-L3 sequence comprising the amino acid sequence of SEQ ID NO: 12. In some aspects, the first antigen-binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 5 and a VL domain comprising the amino acid sequence of SEQ ID NO: 6, and the second antigen-binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 13 and a VL domain comprising the amino acid sequence of SEQ ID NO: 14.

In some aspects, in one of the Fab fragments of the bispecific antibody targeting PD-1 and LAG3 the variable domains VL and VH are replaced by each other so that the VH domain is part of the light chain and the VL domain is part of the heavy chain. In some aspects, in the first Fab fragment the variable domains VL and VH are replaced by each other.

In some aspects, the bispecific antibody comprises a first heavy chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 15, a first light chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 16, a second heavy chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 17, and a second light chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 18. In some aspects, the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 15, a first light chain comprising the amino acid sequence of SEQ ID NO: 16, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 17, and a second light chain comprising the amino acid sequence of SEQ ID NO: 18.

In another aspect, the disclosure provides a bispecific antibody targeting PD-1 and LAG3 for use in a method of treating a subject having a non-squamous Stage IIIB/IIIC NSCLC or a Stage IV NSCLC, wherein the method comprises a dosing regimen comprising a bispecific antibody targeting PD-1 and LAG3, pemetrexed, and carboplatin, wherein the bispecific antibody comprises a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, and wherein the dosing regimen comprises administering to the subject or more dosing cycles of (a) the bispecific antibody, wherein the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 15, a first light chain comprising the amino acid sequence of SEQ ID NO: 16, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 17, and a second light chain comprising the amino acid sequence of SEQ ID NO: 18; (b) pemetrexed, wherein the method comprises administering to the subject the pemetrexed at a dose of 500 mg/m² every three weeks; and (c) carboplatin, wherein the method comprises administering to the subject the carboplatin at a targeted area under the concentration-time curve (AUC) of 5 mg/mL • min every three weeks.

In another aspect, the disclosure provides a bispecific antibody targeting PD-1 and LAG3 for use in a method of treating a subject having a squamous Stage IIIB/IIIC NSCLC or a Stage IV NSCLC, wherein the method comprises a dosing regimen comprising a bispecific antibody targeting PD-1 and LAG3, paclitaxel, and carboplatin, wherein the bispecific antibody comprises a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, and wherein the dosing regimen comprises administering to the subject one or more dosing cycles of (a) the bispecific antibody, wherein the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 15, a first light chain comprising the amino acid sequence of SEQ ID NO: 16, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 17, and a second light chain comprising the amino acid sequence of SEQ ID NO: 18; (b) paclitaxel, wherein the method comprises administering to the subject the paclitaxel at a dose of 200 mg/m² every three weeks; and (c) carboplatin, wherein the method comprises administering to the subject the carboplatin at a targeted AUC of 5 mg/mL • min every three weeks.

In some aspects, the subject is a human.

In another aspect, the disclosure provides the use of a bispecific antibody targeting PD-1 and LAG3 comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigenbinding domain that specifically binds to LAG3 in the manufacture of a medicament for treating a subject or population of subjects having a non-squamous non-small cell lung cancer (NSCLC), wherein the bispecific antibody is formulated for administration simultaneously or separately in combination with (a) pemetrexed and (b) carboplatin, and wherein the treatment comprises administering to the subject or population of subjects a dosing regimen comprising one or more dosing cycles of the medicament, pemetrexed and carboplatin.

In some aspects, the bispecific antibody targeting PD-1 and LAG3 is formulated for administration at a fixed dose of 600 mg every three weeks. In some aspects, pemetrexed is formulated for administration at a dose of 500 mg/m² every three weeks. In some aspects, carboplatin is formulated for administration at a targeted area under the concentration-time curve (AUC) of 5 mg/mL • min every three weeks.

In some aspects, the length of each of the one or more dosing cycles is 21 days, and the bispecific antibody targeting PD-1 and LAG3, pemetrexed, and carboplatin are formulated for administration on Day 1 of each of the one or more dosing cycles.

In some aspects, the bispecific antibody targeting PD-1 and LAG3, the pemetrexed, and the carboplatin are formulated for intravenous administration.

In some aspects, (a) the bispecific antibody targeting PD-1 and LAG3 is formulated for administration over 60 (± 15) minutes in a first dosing cycle;

(b) the dosing regimen comprises one or more additional dosing cycles, and the bispecific antibody targeting PD-1 and LAG3 is formulated for administration over 30 (± 10) minutes in the one or more additional dosing cycles; (c) pemetrexed is formulated for administration over 10 minutes; and/or (d) carboplatin is formulated for administration over 30-60 minutes.

In some aspects, the dosing regimen comprises four dosing cycles.

In some aspects, the dosing regimen further comprises one or more additional dosing cycles of (a) the bispecific antibody targeting PD-1 and LAG3 and (b) pemetrexed.

In some aspects, the dosing regimen comprises at least 5 or at least 10 additional dosing cycles of (a) the bispecific antibody targeting PD-1 and LAG3 and (b) pemetrexed.

In another aspect, the disclosure provides the use of a bispecific antibody targeting PD-1 and LAG3 comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigenbinding domain that specifically binds to LAG3 in the manufacture of a medicament for treating a subject or population of subjects having a squamous NSCLC, wherein the bispecific antibody is formulated for administration simultaneously or separately in combination with (a) paclitaxel and (b) carboplatin, and wherein the treatment comprises administering to the subject or population of subjects a dosing regimen comprising one or more dosing cycles of the medicament, paclitaxel and carboplatin.

In some aspects, the bispecific antibody targeting PD-1 and LAG3 is formulated for administration at a fixed dose of 600 mg every three weeks.

In some aspects, the paclitaxel is formulated for administration at a dose of 200 mg/m² every three weeks. In some aspects, the carboplatin is formulated for administration at a targeted AUC of 5 mg/mL • min every three weeks.

In some aspects, the length of each of the one or more dosing cycles is 21 days, and the bispecific antibody targeting PD-1 and LAG3, the paclitaxel, and the carboplatin are formulated for administration on Day 1 of each of the one or more dosing cycles.

In some aspects, the bispecific antibody targeting PD-1 and LAG3, the paclitaxel, and the carboplatin are formulated for intravenous administration.

In some aspects, (a) the bispecific antibody over 60 (± 15) minutes is formulated for administration in a first dosing cycle;

(b) the dosing regimen comprises one or more additional dosing cycles, and the bispecific antibody targeting PD-1 and LAG3 is formulated for administration over 30 (± 10) minutes in the one or more additional dosing cycles; (c) paclitaxel is formulated for administration over 3 hours; and/or (d) carboplatin is formulated for administration over 30-60 minutes.

In some aspects, the dosing regimen comprises four dosing cycles.

In some aspects, the dosing regimen further comprises one or more additional dosing cycles of the bispecific antibody targeting PD-1 and LAG3.

In some aspects, the dosing regimen comprises at least 5 or at least 10 additional dosing cycles of the bispecific antibody targeting PD-1 and LAG3.

In some aspects, the treatment results in an increase in progression-free survival (PFS) as compared to a reference PFS. In some aspects, the reference PFS is a PFS of a population of subjects who have received a control therapy.

In some aspects, the treatment results in an increase in objective response rate (ORR) in a population of subjects treated according to the method as compared to a reference ORR. In some aspects, reference ORR is an ORR of a population of subjects who have received a control therapy.

In some aspects, the treatment results in an increase in overall survival (OS) as compared to a reference OS. In some aspects, the reference OS is an OS of a population of subjects who have received a control therapy.

In some aspects, the treatment results in an increase in duration of response (DOR) as compared to a reference DOR. In some aspects, the reference DOR is a DOR of a population of subjects who have received a control therapy. In some aspects, (a) the subject has a non-squamous NSCLC, and the control therapy comprises pembrolizumab, pemetrexed, and carboplatin and does not comprise the bispecific antibody; or(b) the subject has a squamous NSCLC, and the control therapy comprises pembrolizumab, paclitaxel, and carboplatin and does not comprise the bispecific antibody.

In some aspects, the bispecific antibody targeting PD-1 and LAG3 comprises a first antigenbinding domain that specifically binds to PD-1 comprising a heavy chain variable (VH) domain comprising:

(ii) an HVR-H2 sequence comprising the amino acid sequence GGR, and

(iii) an HVR-H3 sequence comprising an amino acid sequence of SEQ ID NO: 2; and a light chain variable (VL) domain comprising

(i) an HVR-L1 sequence comprising the amino acid sequence of SEQ ID NO: 3;

(ii) an HVR-L2 sequence comprising the amino acid sequence RSS, and

(iii) an HVR-L3 sequence comprising the amino acid sequence of SEQ ID NO: 4.

In some aspects, the bispecific antibody targeting PD-1 and LAG3 comprises a second antigenbinding domain that specifically binds to LAG3 comprising a VH domain comprising:

(i) an HVR-H1 sequence comprising the amino acid sequence of SEQ ID NO: 7,

(ii) an HVR-H2 sequence comprising the amino acid sequence of SEQ ID NO: 8, and

(iii) an HVR-H3 sequence comprising an amino acid sequence of SEQ ID NO: 9; and a VL domain comprising:

(i) an HVR-L1 sequence comprising the amino acid sequence of SEQ ID NO: 10,

(ii) an HVR-L2 sequence comprising the amino acid sequence of SEQ ID NO: 11 , and

(iii) an HVR-L3 sequence comprising the amino acid sequence of SEQ ID NO: 12.

In some aspects, the bispecific antibody targeting PD-1 and LAG3 comprises:

(a) an Fc domain of human IgG 1 subclass with the amino acid mutations L234A, L235A, and P329G (numbering according to Kabat EU index); and/or

(b) an Fc domain comprising a modification promoting the association of the first and second subunit of the Fc domain.

In some aspects, the bispecific antibody targeting PD-1 and LAG3 comprises a first Fab fragment comprising said first antigen binding domain specifically binding to PD1 comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 5 and a VL domain comprising the amino acid sequence of SEQ ID NO: 6; and a second Fab fragment comprising the second antigen binding domain specifically binding to LAG3 comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 13 and a VL domain comprising the amino acid sequence of SEQ ID NO: 14, and an Fc domain of human IgG 1 subclass with the amino acid mutations L234A, L235A, and P329G (numbering according to Kabat EU index).

In some aspects, the bispecific antibody targeting PD-1 and LAG3 comprises a first heavy chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 15, a first light chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 16, a second heavy chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 17, and a second light chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 18.

In some aspects, the bispecific antibody targeting PD-1 and LAG3 comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 15, a first light chain comprising the amino acid sequence of SEQ ID NO: 16, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 17, and a second light chain comprising the amino acid sequence of SEQ ID NO: 18.

In some aspects, the bispecific antibody targeting PD-1 and LAG3 is tobemstomig.

In some aspects, the disclosure provides the use of a bispecific antibody targeting PD-1 and LAG3 comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3 in the manufacture of a medicament for treating a subject or population of subjects a non-squamous Stage IIIB/IIIC NSCLC or a Stage IV NSCLC, wherein the treatment comprises administering to the subject a dosing regimen comprising one or more dosing cycles of:

(a) the bispecific antibody targeting PD-1 and LAG3 administered at a fixed dose of 600 mg every three weeks, wherein the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 15, a first light chain comprising the amino acid sequence of SEQ ID NO: 16, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 17, and a second light chain comprising the amino acid sequence of SEQ ID NO: 18;

(b) pemetrexed administered at a dose of 500 mg/m² every three weeks; and

(c) carboplatin administered at a targeted area under the concentration-time curve (AUC) of 5 mg/mL • min every three weeks.

In some aspects, the disclosure provides the use of a bispecific antibody targeting PD-1 and LAG3 comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigenbinding domain that specifically binds to LAG3 in the manufacture of a medicament for treating a subject or population of subjects a squamous Stage IIIB/IIIC NSCLC or a Stage IV NSCLC, wherein the treatment comprises administering to the subject a dosing regimen comprising one or more dosing cycles of:

(b) paclitaxel administered at a dose of 200 mg/m² every three weeks; and (c) carboplatin administered at a targeted AUC of 5 mg/mL • min every three weeks.

In all these aspects, the subject may be a human.

In another aspect, the disclosure provides a method for treating a subject having a triple-negative breast cancer (TNBC), wherein the method comprises a dosing regimen comprising concurrently administering to the subject: (a) one or more dosing cycles of a bispecific antibody targeting PD-1 and LAG3 comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigenbinding domain that specifically binds to LAG3; and (b) one or more dosing cycles of nab-paclitaxel.

In some aspects, the subject has not previously received a systemic anti-cancer therapy for locally advanced, unresectable or metastatic TNBC.

In some aspects, the subject has not previously been treated with an anti-LAG3 therapy, a CD137 agonist, or an anti-CTLA therapeutic antibody.

In some aspects, the length of each of the one or more dosing cycles of the bispecific antibody is 21 days.

In some aspects, the method comprises administering to the subject the bispecific antibody on Day 1 of each of the one or more dosing cycles.

In some aspects, the method comprises administering to the subject the bispecific antibody intravenously. In some aspects, (a) the bispecific antibody is administered over 60 (± 15) minutes in a first dosing cycle; and/or (b) the method comprises one or more additional dosing cycles, and the bispecific antibody is administered over 30 (± 10) minutes in the one or more additional dosing cycles.

In some aspects, the method comprises administering to the subject the nab-paclitaxel at a dose of 100 mg/m² once a week for three weeks, followed by 1 week off.

In some aspects, the method comprises administering to the subject the bispecific antibody at a fixed dose of 600 mg every three weeks and the nab-paclitaxel at a dose of 100 mg/m² once a week for three weeks, followed by 1 week off.

In some aspects, the length of each of the one or more dosing cycles of nab-paclitaxel is 28 days.

In some aspects, the method comprises administering to the subject the nab-paclitaxel on Days 1 , 8, and 15 of each of the one or more dosing cycles.

In some aspects, the method comprises administering to the subject the nab-paclitaxel intravenously. In some aspects, the nab-paclitaxel is administered over 30 minutes.

In some aspects, on days on which the bispecific antibody and the nab-paclitaxel are administered on the same day, the method comprises administering to the subject the bispecific antibody before the nab-paclitaxel.

In some aspects, the TNBC is a locally advanced, unresectable or metastatic TNBC.

In some aspects, the TNBC is a PD-L1 -positive TNBC.

In some aspects, the PD-L1 -positive TNBC has a PD-L1 combined positive score (CPS) of > 10, as measured using the pharmDx 22C3 IHC assay. In some aspects, the PD-L1 -positive TNBC has a PD-L1 tumor area positivity score (TAP) of > 5%, as measured using the Ventana SP263 IHC assay.

In some aspects, the PD-L1 -positive TNBC has a PD-L1 -positive immune cell (IC) fraction of > 1%, as measured using the Ventana SP142 IHC assay.

In some aspects, the dosing regimen comprises at least 5 or at least 10 dosing cycles of (a) the bispecific antibody and (b) nab-paclitaxel.

In some aspects, the method results in an increase in PFS rate at 12 months as compared to a reference PFS rate at 12 months. In some aspects, the reference PFS rate is a PFS rate of a population of subjects who have received a control therapy.

In some aspects, the method results in an increase in OS rate at 12 months as compared to a reference OS rate at 12 months. In some aspects, the reference OS rate is an OS rate of a population of subjects who have received a control therapy.

In some aspects, the control therapy comprises pembrolizumab and nab-paclitaxel and does not comprise the bispecific antibody.

In some aspects, the bispecific antibody targeting PD-1 and LAG3 comprises a first antigenbinding domain that specifically binds to PD-1 comprising a heavy chain variable (VH) domain comprising (i) an HVR-H1 sequence comprising the amino acid sequence of SEQ ID NO: 1 , (ii) an HVR-H2 sequence comprising the amino acid sequence GGR, and (iii) an HVR-H3 sequence comprising an amino acid sequence of SEQ ID NO: 2; and a light chain variable (VL) domain comprising (i) an HVR-L1 sequence comprising the amino acid sequence of SEQ ID NO: 3; (ii) an HVR-L2 sequence comprising the amino acid sequence RSS, and (iii) an HVR-L3 sequence comprising the amino acid sequence of SEQ ID NO: 4.

In some aspects, the bispecific antibody targeting PD-1 and LAG3 comprises a first Fab fragment comprising said first antigen binding domain specifically binding to PD1 comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 5 and a VL domain comprising the amino acid sequence of SEQ ID NO: 6 and a second Fab fragment comprising the second antigen binding domain specifically binding to LAG3 comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 13 and a VL domain comprising the amino acid sequence of SEQ ID NO: 14, and an Fc domain of human IgG 1 subclass with the amino acid mutations L234A, L235A, and P329G (numbering according to Kabat EU index).

In another aspect, the disclosure provides a method for treating a subject having a locally advanced, unresectable or metastatic TNBC, wherein the method comprises a dosing regimen comprising concurrently administering to the subject (a) one or more dosing cycles of a bispecific antibody targeting PD-1 and LAG3 comprising a first antigen-binding domain that specifically binds to PD- 1 and a second antigen-binding domain that specifically binds to LAG3, wherein the method comprises administering to the subject the bispecific antibody at a fixed dose of 600 mg every three weeks, and wherein the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 15, a first light chain comprising the amino acid sequence of SEQ ID NO: 16, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 17, and a second light chain comprising the amino acid sequence of SEQ ID NO: 18; and (b) one or more dosing cycles of nab-paclitaxel, wherein the method comprises administering to the subject the nab-paclitaxel at a dose of 100 mg/m² once a week for three weeks, followed by 1 week off.

In another aspect, the disclosure provides a bispecific antibody targeting PD-1 and LAG3 for use in a method of treating a subject having a triple-negative breast cancer (TNBC), wherein the method comprises a dosing regimen comprising a bispecific antibody targeting PD-1 and LAG3 and nab- paclitaxel, wherein the bispecific antibody comprises a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, and wherein the dosing regimen comprises concurrently administering to the subject (a) one or more dosing cycles of the bispecific antibody; and (b) one or more dosing cycles of nab-paclitaxel.

In some aspects, the method comprises administering to the subject the bispecific antibody intravenously. In some aspects, (a) the bispecific antibody is to be administered over 60 (± 15) minutes in a first dosing cycle; and/or (b) the method comprises one or more additional dosing cycles, and the bispecific antibody is to be administered over 30 (± 10) minutes in the one or more additional dosing cycles. In some aspects, the method comprises administering to the subject the nab-paclitaxel at a dose of 100 mg/m² once a week for three weeks, followed by 1 week off.

In some aspects, the method comprises administering to the subject the nab-paclitaxel intravenously. In some aspects, the nab-paclitaxel is to be administered over 30 minutes.

In some aspects, on days on which the bispecific antibody and the nab-paclitaxel are to be administered on the same day, the method comprises administering to the subject the bispecific antibody before the nab-paclitaxel.

In some aspects, the TNBC is a PD-L1 -positive TNBC.

In some aspects, the PD-L1 -positive TNBC has a PD-L1 combined positive score (CPS) of > 10, as measured using the pharmDx 22C3 IHC assay.

In some aspects, the PD-L1 -positive TNBC has a PD-L1 tumor area positivity score (TAP) of > 5%, as measured using the Ventana SP263 IHC assay.

In some aspects, the method results in an increase in PFS rate at 12 months as compared to a reference PFS rate at 12 months. In some aspects, the reference PFS rate is a PFS rate of a population of subjects who have received a control therapy. In some aspects, the method results in an increase in OS rate at 12 months as compared to a reference OS rate at 12 months. In some aspects, the reference OS rate is an OS rate of a population of subjects who have received a control therapy.

In another aspect, the disclosure provides a bispecific antibody targeting PD-1 and LAG3 for use in a method of treating a subject having a locally advanced, unresectable or metastatic TNBC, wherein the method comprises a dosing regimen comprising a bispecific antibody targeting PD-1 and LAG3 and nab-paclitaxel, wherein the bispecific antibody targeting PD-1 and LAG3 comprises a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, and wherein the dosing regimen comprises concurrently administering to the subject (a) one or more dosing cycles of the bispecific antibody at a fixed dose of 600 mg every three weeks, wherein the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 15, a first light chain comprising the amino acid sequence of SEQ ID NO: 16, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 17, and a second light chain comprising the amino acid sequence of SEQ ID NO: 18; and (b) one or more dosing cycles of nab-paclitaxel, wherein the method comprises administering to the subject the nab-paclitaxel at a dose of 100 mg/m² once a week for three weeks, followed by 1 week off.

In some aspects, the subject is a human. In another aspect, the disclosure provides the use of a bispecific antibody targeting PD-1 and LAG3 comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigenbinding domain that specifically binds to LAG3 in the manufacture of a medicament for treating a subject or population of subjects having a triple-negative breast cancer (TNBC), wherein the bispecific antibody is formulated for concurrent administration in combination with nab-paclitaxel, and wherein the treatment comprises administering to the subject or population of subjects a dosing regimen comprising one or more dosing cycles of the medicament and nab-paclitaxel.

In some aspects, the subject has not previously received a systemic anti-cancer therapy for locally advanced, unresectable or metastatic TNBC. In some aspects, the subject has not previously been treated with an anti-LAG3 therapy, a CD137 agonist, or an anti-CTLA therapeutic antibody.

In some aspects, the length of each of the one or more dosing cycles of the bispecific antibody is 21 days. In some aspects, the bispecific antibody targeting PD-1 and LAG3 is formulated for administration on Day 1 of each of the one or more dosing cycles.

In some aspects, the bispecific antibody targeting PD-1 and LAG3 is formulated for intravenous administration.

In some aspects, the bispecific antibody targeting PD-1 and LAG3 is formulated for administration over 60 (± 15) minutes in a first dosing cycle; and/or the bispecific antibody targeting PD-1 and LAG3 is formulated for administration over 30 (± 10) minutes in one or more additional dosing cycles. In some aspects, the nab-paclitaxel is formulated for administration at a dose of 100 mg/m² once a week for three weeks, followed by 1 week off. In some aspects, the bispecific antibody targeting PD-1 and LAG3 is formulated for administration at a fixed dose of 600 mg every three weeks and nab-paclitaxel is formulated for administration at a dose of 100 mg/m² once a week for three weeks, followed by 1 week off.

In some aspects, the length of each of the one or more dosing cycles of nab-paclitaxel is 28 days. In some aspects, nab-paclitaxel is formulated for administration on Days 1 , 8, and 15 of each of the one or more dosing cycles.

In some aspects, nab-paclitaxel is formulated for intravenous administration. In some aspects, nab-paclitaxel is formulated for administration over 30 minutes.

In some aspects, on days on which the bispecific antibody and the nab-paclitaxel are to be administered on the same day, the bispecific antibody is formulated for administration before the nab- paclitaxel.

In some aspects, the TNBC is a locally advanced, unresectable or metastatic TNBC. In some aspects, the subject does not have any symptomatic, untreated, or actively progressing central nervous system (CNS) metastases.

In some aspects, the TNBC is a PD-L1 -positive TNBC. In some aspects, the PD-L1 -positive TNBC has a PD-L1 combined positive score (CPS) of > 10, as measured using the pharmDx 22C3 IHC assay. In some aspects, the PD-L1 -positive TNBC has a PD-L1 tumor area positivity score (TAP) of > 5%, as measured using the Ventana SP263 IHC assay. In some aspects, the PD-L1 -positive TNBC has a PD-L1 -positive immune cell (IC) fraction of > 1 %, as measured using the Ventana SP142 IHC assay.

In some aspects, the dosing regimen comprises at least 5 or at least 10 dosing cycles of (a) the bispecific antibody targeting PD-1 and LAG3 and (b) nab-paclitaxel.

In some aspects, the treatment results in an increase in objective response rate (ORR) in a population of subjects treated according to the method as compared to a reference ORR. In some aspects, the reference ORR is an ORR of a population of subjects who have received a control therapy.

In some aspects, the treatment results in an increase in duration of response (DOR) as compared to a reference DOR. In some aspects, the reference DOR is a DOR of a population of subjects who have received a control therapy.

In some aspects, the treatment results in an increase in PFS rate at 12 months as compared to a reference PFS rate at 12 months. In some aspects, the reference PFS rate is a PFS rate of a population of subjects who have received a control therapy.

In some aspects, the treatment results in an increase in OS rate at 12 months as compared to a reference OS rate at 12 months. In some aspects, the reference OS rate is a OS rate of a population of subjects who have received a control therapy.

In some aspects, the control therapy comprises pembrolizumab and nab-paclitaxel and does not comprise the bispecific antibody targeting PD-1 and LAG3.

(ii) an HVR-H2 sequence comprising the amino acid sequence GGR, and

(i) an HVR-L1 sequence comprising the amino acid sequence of SEQ ID NO: 3;

(ii) an HVR-L2 sequence comprising the amino acid sequence RSS, and

(iii) an HVR-L3 sequence comprising the amino acid sequence of SEQ ID NO: 4.

In some aspects, the bispecific antibody targeting PD-1 and LAG3 comprises a second antigenbinding domain that specifically binds to LAG3 comprising a VH domain comprising: (i) an HVR-H1 sequence comprising the amino acid sequence of SEQ ID NO: 7,

(ii) an HVR-H2 sequence comprising the amino acid sequence of SEQ ID NO: 8, and

(i) an HVR-L1 sequence comprising the amino acid sequence of SEQ ID NO: 10,

(ii) an HVR-L2 sequence comprising the amino acid sequence of SEQ ID NO: 1 1 , and

(iii) an HVR-L3 sequence comprising the amino acid sequence of SEQ ID NO: 12.

In some aspects, the bispecific antibody targeting PD-1 and LAG3 comprises:(a) an Fc domain of human IgG 1 subclass with the amino acid mutations L234A, L235A, and P329G (numbering according to Kabat EU index); and/or(b) an Fc domain comprising a modification promoting the association of the first and second subunit of the Fc domain.

In some aspects, the disclosure provides the use of a bispecific antibody targeting PD-1 and LAG3 comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3 in the manufacture of a medicament for treating a subject or population of subjects having a locally advanced, unresectable or metastatic TNBC, wherein the treatment comprises a dosing regimen comprising concurrently administering to the subject:

(a) one or more dosing cycles of administration of the bispecific antibody targeting PD-1 and LAG3 at a fixed dose of 600 mg every three weeks, wherein the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 15, a first light chain comprising the amino acid sequence of SEQ ID NO: 16, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 17, and a second light chain comprising the amino acid sequence of SEQ ID NO: 18; and

(b) one or more dosing cycles of administration of nab-paclitaxel at a dose of 100 mg/m² once a week for three weeks, followed by 1 week off.

In all these aspects, the subject may be a human.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is a flow chart showing the design of the BO44178 phase II clinical trial of RO7247669 plus platinum-based chemotherapy versus pembrolizumab plus platinum-based chemotherapy in patients with previously untreated locally advanced or metastatic non-small cell lung cancer (NSCLC).

ADA = anti-drug antibody; DOR = duration of response; ECOG PS= Eastern Cooperative Oncology Group Performance Status; IMC = lnternal Monitoring Committee; lnv = investigator;; NSCLC = non-small cell lung cancer; NSQ = non-squamous; ORR = objective response rate; OS = overall survival;

PD = progressive disease; PD-L1 = programmed death-ligand 1 ; PFS = progression-free survival; PK= pharmacokinetic; PRO= patient-reported outcome; R = randomization; SQ = squamous.

Fig. 2 is a flow chart showing the design of the CO44194 phase II clinical trial of RO7247669 combined with nab-paclitaxel compared with pembrolizumab combined with nab-paclitaxel in patients with previously untreated, PD-L1 -positive, locally-advanced unresectable or metastatic triple negative breast cancer (TNBC). 1 L = first line; CPS = Combined Positive Score; eTNBC = early triple-negative breast cancer; IMG = Internal Monitoring Committee; PD-L1 = programmed death ligand-1 ;

Q3 W= every 3 weeks; R = randomization; TAP = Tumor Area Positivity. ^a Safety run-in: After 12th participant reaches approximately 6 weeks after first study treatment.

Fig. 3A is a schematic diagram showing the detailed design of Year One of the CO44194 phase II clinical trial. ADA = anti-drug antibody; PK = pharmacokinetic.

Fig. 3B is a schematic diagram showing the detailed design of Year Two onwards of the CO44194 phase II clinical trial.

Fig. 3C is a schematic diagram showing the detailed design of the follow-up period of the CO44194 phase II clinical trial.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides therapeutic methods and compositions for treatment of non-small cell lung cancer (NSCLC) or triple-negative breast cancer (TNBC). Compositions, uses, and kits involving such combinations and/or dosing regimens are also provided herein.

I. Definitions

The following abbreviations are used herein:

The term “about” as used herein refers to the usual error range for the respective value readily known to the skilled person in this technical field. Reference to “about” a value or parameter herein includes (and describes) aspects that are directed to that value or parameter per se. For example, description referring to “about X” includes description of “X.”

The term “PD-1 axis binding antagonist” refers to a molecule that inhibits the interaction of a PD- 1 axis binding partner with either one or more of its binding partners, so as to remove T-cell dysfunction resulting from signaling on the PD-1 signaling axis, with a result being to restore or enhance T-cell function (e.g., proliferation, cytokine production, and/or target cell killing). As used herein, a PD-1 axis binding antagonist includes a PD-L1 binding antagonist, a PD-1 binding antagonist, and a PD-L2 binding antagonist. In some instances, the PD-1 axis binding antagonist includes a PD-L1 binding antagonist or a PD-1 binding antagonist. In a preferred aspect, the PD-1 axis binding antagonist is a PD-L1 binding antagonist.

The term “PD-L1 binding antagonist” refers to a molecule that decreases, blocks, inhibits, abrogates, or interferes with signal transduction resulting from the interaction of PD-L1 with either one or more of its binding partners, such as PD-1 and/or B7-1 . In some instances, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partners. In a specific aspect, the PD-L1 binding antagonist inhibits binding of PD-L1 to PD-1 and/or B7-1 . In some instances, the PD-L1 binding antagonists include anti-PD-L1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners, such as PD- 1 and/or B7-1 . In one instance, a PD-L1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-L1 so as to render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some instances, the PD-L1 binding antagonist binds to PD-L1 . In some instances, a PD-L1 binding antagonist is an anti-PD-L1 antibody (e.g., an anti-PD-L1 antagonist antibody). Exemplary anti-PD-L1 antagonist antibodies include atezolizumab, MDX-1105, MEDI4736 (durvalumab), MSB0010718C (avelumab), SHR-1316, CS1001 , envafolimab, TQB2450, ZKAB001 , LP- 002, CX-072, IMC-001 , KL-A167, APL-502, cosibelimab, lodapolimab, FAZ053, TG-1501 , BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311 , RC98, PDL-GEX, KD036, KY1003, YBL-007, and HS-636. In some aspects, the anti-PD-L1 antibody is atezolizumab, MDX-1105, MEDI4736 (durvalumab), or MSB0010718C (avelumab). In one specific aspect, the PD-L1 binding antagonist is MDX-1105. In another specific aspect, the PD-L1 binding antagonist is MEDI4736 (durvalumab). In another specific aspect, the PD-L1 binding antagonist is MSB0010718C (avelumab). In other aspects, the PD-L1 binding antagonist may be a small molecule, e.g., GS-4224, INCB086550, MAX-10181 , INCB090244, CA-170, or ABSK041 , which in some instances may be administered orally. Other exemplary PD-L1 binding antagonists include AVA-004, MT-6035, VXM10, LYN192, GB7003, and JS- 003. In a preferred aspect, the PD-L1 binding antagonist is atezolizumab.

The term “PD-1 binding antagonist” refers to a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-1 with one or more of its binding partners, such as PD-L1 and/or PD-L2. PD-1 (programmed death 1 ) is also referred to in the art as “programmed cell death 1 ,” “PDCD1 ,” “CD279,” and “SLEB2.” An exemplary human PD-1 is shown in UniProtKB/Swiss-Prot Accession No. Q15116. In some instances, the PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to one or more of its binding partners. In a specific aspect, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and/or PD-L2. For example, PD-1 binding antagonists include anti-PD-1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-1 with PD-L1 and/or PD-L2. In one instance, a PD-1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-1 so as render a dysfunctional T- cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some instances, the PD-1 binding antagonist binds to PD-1 . In some instances, the PD-1 binding antagonist is an anti-PD-1 antibody (e.g., an anti-PD-1 antagonist antibody). Exemplary anti-PD-1 antagonist antibodies include nivolumab, pembrolizumab, MEDI-0680, PDR001 (spartalizumab), REGN2810 (cemiplimab), BGB-108, prolgolimab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, retifanlimab, sasanlimab, penpulimab, CS1003, HLX10, SCT-I10A, zimberelimab, balstilimab, genolimzumab, Bl 754091 , cetrelimab, YBL-006, BAT1306, HX008, budigalimab, AMG 404, CX-188, JTX-4014, 609A, Sym021 , LZM009, F520, SG001 , AM0001 , ENUM 244C8, ENUM 388D4, STI-1110, AK-103, and hAb21 . In a specific aspect, a PD-1 binding antagonist is MDX-1106 (nivolumab). In another specific aspect, a PD-1 binding antagonist is MK-3475 (pembrolizumab). In another specific aspect, a PD-1 binding antagonist is a PD-L2 Fc fusion protein, e.g., AMP-224. In another specific aspect, a PD-1 binding antagonist is MED1 -0680. In another specific aspect, a PD-1 binding antagonist is PDR001 (spartalizumab). In another specific aspect, a PD-1 binding antagonist is REGN2810 (cemiplimab). In another specific aspect, a PD-1 binding antagonist is BGB-108. In another specific aspect, a PD-1 binding antagonist is prolgolimab. In another specific aspect, a PD-1 binding antagonist is camrelizumab. In another specific aspect, a PD-1 binding antagonist is sintilimab. In another specific aspect, a PD-1 binding antagonist is tislelizumab. In another specific aspect, a PD-1 binding antagonist is toripalimab. Other additonal exemplary PD-1 binding antagonists include BION-004, CB201 , AUNP-012, ADG104, and LBL-006. In a particular aspect, a PD-1 binding antagonist antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 5 and a VL domain comprising the amino acid sequence of SEQ ID NO: 6.

The term “PD-L2 binding antagonist” refers to a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-L2 with either one or more of its binding partners, such as PD-1 . PD-L2 (programmed death ligand 2) is also referred to in the art as “programmed cell death 1 ligand 2,” “PDCD1 LG2,” “CD273,” “B7-DC,” “Btdc,” and “PDL2.” An exemplary human PD-L2 is shown in UniProtKB/Swiss-Prot Accession No. Q9BQ51 . In some instances, a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to one or more of its binding partners. In a specific aspect, the PD-L2 binding antagonist inhibits binding of PD-L2 to PD-1 . Exemplary PD-L2 antagonists include anti-PD-L2 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L2 with either one or more of its binding partners, such as PD-1 . In one aspect, a PD-L2 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-L2 so as render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some aspects, the PD-L2 binding antagonist binds to POUT In some aspects, a PD-L2 binding antagonist is an immunoadhesin. In other aspects, a PD-L2 binding antagonist is an anti-PD-L2 antagonist antibody.

The terms “programmed death ligand 1 ” and “PD-L1” refer herein to native sequence human PD- L1 polypeptide. Native sequence PD-L1 polypeptides are provided under Uniprot Accesion No. Q9NZQ7. For example, the native sequence PD-L1 may have the amino acid sequence as set forth in Uniprot Accesion No. Q9NZQ7-1 (isoform 1 ) (SEQ ID NO: 38). In another example, the native sequence PD-L1 may have the amino acid sequence as set forth in Uniprot Accesion No. Q9NZQ7-2 (isoform 2). In yet another example, the native sequence PD-L1 may have the amino acid sequence as set forth in Uniprot Accesion No. Q9NZQ7-3 (isoform 3). PD-L1 is also referred to in the art as “programmed cell death 1 ligand 1 ,” “PDCD1 LG1 ,” “CD274,” “B7-H,” and “PDL1 .”

The Kabat numbering system is generally used when referring to a residue in the variable domain (approximately residues 1 -107 of the light chain and residues 1 -113 of the heavy chain) (e.g., Kabat et al., Sequences of Immunological Interest. 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991 )). The “EU numbering system” or “EU index” is generally used when referring to a residue in an immunoglobulin heavy chain constant region (e.g., the EU index reported in Kabat et al., supra). The “EU index as in Kabat” refers to the residue numbering of the human IgG 1 EU antibody.

The term “cancer” refers to a disease caused by an uncontrolled division of abnormal cells in a part of the body. In one instance, the cancer is a non-small cell lung cancer (NSCLC), e.g., a squamous or non-squamous NSCLC, e.g., a Stage IIIB/IIIC or Stage IV squamous or non-squamous NSCLC). In another instance, the cancer is a breast cancer (e.g., a triple-negative breast cancer (TNBC, e.g., a locally advanced, unresectable or metastatic TNBC)). Cancers include solid tumor cancers and non-solid tumor cancers and locally advanced or metastatic cancers (e.g., locally advanced or metastatic tumors). Examples of cancer include but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include, but are not limited to urothelial carcinoma (UC), including locally advanced and metastatic UC (mUC), bladder cancer (e.g., muscle invasive bladder cancer (MIBC) and non-muscle invasive bladder cancer (NMIBC), e.g., BCG-refractory NMIBC), MIBC urothelial bladder cancer (UBC); kidney or renal cancer (e.g., renal cell carcinoma (RCC)); cancer of the urinary tract; lung cancer, such as small cell lung cancer (SCLC), which includes extensive stage SCLC (ES-SCLC); non-small cell lung cancer (NSCLC), which includes squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage 11 IB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC), adenocarcinoma of the lung, or squamous cell cancer (e.g., epithelial squamous cell cancer (e.g., squamous carcinoma of the lung); pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC), e.g., metastatic PDAC)); head and neck cancer (e.g., SCCHN, e.g., recurrent/metastatic PD-L1 -positive SCCHN, and head and neck squamous cell cancer (HNSCC); ovarian cancer (OC); esophageal cancer; cancer of the peritoneum; hepatocellular cancer; gastric cancer (GO) (e.g., gastroesophageal junction (GEJ) cancer) or stomach cancer, including gastrointestinal cancer and gastrointestinal stromal cancer; glioblastoma; cancer of the urinary tract; hepatoma; breast cancer (e.g., HER2+ breast cancer and triple-negative breast cancer (TNBC (e.g., early TNBC (eTNBC)), which are estrogen receptors (ER-), progesterone receptors (PgR-), and HER2 (HER2-) negative); prostate cancer, such as castration-resistant prostate cancer (CRPC); cancer of the peritoneum; hepatocellular cancer; gastric or stomach cancer, including gastrointestinal cancer and gastrointestinal stromal cancer; pancreatic cancer (e.g., pancreatic ductal adenocarcinoma (PDAC)); glioblastoma; cervical cancer (e.g., a Stage IVB, metastatic, recurrent, or persistent cervical cancer, e.g., a metastatic and/or recurrent PD-L1 -positive cervical carcinoma); ovarian cancer; hepatoma; colon cancer; rectal cancer; colorectal cancer (CRC; e.g., CRC with microsatellite-stable (MSS) and microsatellite instability (MSI) low (MSI-Low)); endometrial or uterine carcinoma; salivary gland carcinoma; prostate cancer; vulval cancer; thyroid cancer; hepatic carcinoma; anal carcinoma; penile carcinoma; melanoma, including superficial spreading melanoma, lentigo maligna melanoma, acral lentiginous melanomas, and nodular melanomas; multiple myeloma and B-cell lymphoma (including low grade/follicular non-Hodgkin’s lymphoma (NHL)); small lymphocytic (SL) NHL; intermediate grade/follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic NHL; high grade small non-cleaved cell NHL; bulky disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom’s Macroglobulinemia); chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); acute myologenous leukemia (AML); hairy cell leukemia; chronic myeloblastic leukemia (CML); post-transplant lymphoproliferative disorder (PTLD); and myelodysplastic syndromes (MDS), as well as abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), Meigs’ syndrome, brain cancer, head and neck cancer, and associated metastases.

In some instances, the cancer (e.g., NSCLC (e.g., squamous or non-squamous NSCLC, e.g., Stage IIIB/IIIC or Stage IV squamous or non-squamous NSCLC) or TNBC (e.g., locally advanced, unresectable or metastatic TNBC)) is a tumor having a tumor microenvironment comprising LAG3- expressing CD8+ T cells.

In some instances, the cancer may be unresectable (e.g., unresectable locally advanced or metastatic cancer). The term “tumor” refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. The terms “cancer,” “cancerous,” “cell proliferative disorder,” “proliferative disorder,” and “tumor” are not mutually exclusive as referred to herein.

A “tumor cell,” as used herein, refers to any tumor cell present in a tumor or a sample thereof. Tumor cells may be distinguished from other cells that may be present in a tumor sample, for example, stromal cells and tumor-infiltrating immune cells, using methods known in the art and/or described herein.

“Tumor immunity” refers to the process in which tumors evade immune recognition and clearance. Thus, as a therapeutic concept, tumor immunity is “treated” when such evasion is attenuated, and the tumors are recognized and attacked by the immune system. Examples of tumor recognition include tumor binding, tumor shrinkage, and tumor clearance.

As used herein, by “metastasis” is meant the spread of cancer from its primary site to other places in the body. Cancer cells can break away from a primary tumor, penetrate into lymphatic and blood vessels, circulate through the bloodstream, and grow in a distant focus (metastasize) in normal tissues elsewhere in the body. Metastasis can be local or distant. Metastasis is a sequential process, contingent on tumor cells breaking off from the primary tumor, traveling through the bloodstream, and stopping at a distant site. At the new site, the cells establish a blood supply and can grow to form a lifethreatening mass. Both stimulatory and inhibitory molecular pathways within the tumor cell regulate this behavior, and interactions between the tumor cell and host cells in the distant site are also significant.

As used herein, “treating” comprises effective cancer treatment with an effective amount of a therapeutic agent (e.g., a bispecific antibody targeting PD-1 and LAG3) or a combination of therapeutic agents (e.g., a bispecific antibody targeting PD-1 and LAG3 and a chemotherapeutic agent, e.g., nab- paclitaxel). Treating herein includes, inter alia, adjuvant therapy, neoadjuvant therapy, non-metastatic cancer therapy (e.g., locally advanced cancer therapy), and metastatic cancer therapy. The treatment may be first-line treatment (e.g., the patient may be previously untreated or not have received prior systemic therapy), or second line or later treatment.

Herein, an “effective amount” refers to the amount of a therapeutic agent (e.g., a bispecific antibody targeting PD-1 and LAG3) or a combination of therapeutic agents (e.g., a bispecific antibody targeting PD-1 and LAG3 and one or more chemotherapeutic agents, e.g., (a) one or both of pemetrexed and carboplatin, (b) one or both of paclitaxel and carboplatin, or (c) nab-paclitaxel), that achieves a therapeutic result. In some examples, the effective amount of a therapeutic agent or a combination of therapeutic agents is the amount of the agent or of the combination of agents that achieves a clinical endpoint of improved progression-free survival (PFS), improved PFS rate (e.g., improved PFS rate at 12 months), improved objective response rate (ORR), improved overall survival (OS), improved OS rate (e.g., improved OS rate at 12 months), improved pathologic response rate (PRR), improved disease control rate (DCR), a complete response (CR), a pathological complete response (pCR), a partial response (PR), improved survival (e.g., disease-free survival (DFS), and/or and/or improved duration of response (DOR).

As used herein, “complete response” and “CR” refer to disappearance of all target lesions. As used herein, “partial response” and “PR” refer to at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline SLD prior to treatment, in the absence of CR.

As used here, “progressive disease” and “PD” refer to at least a 20% increase in the SLD of target lesions, taking as reference the smallest sum of diameters at prior timepoints, including baseline. The appearance of one or more new lesions may also be considered PD.

As used herein, “stable disease” and “SD” refers to neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum.

As used herein, “disease control rate” and “DCR” refer to the percentage of patients cancer who have achieved CR, PR, and stable disease (SD). For example, DCR may be defined as the proportion of patients with SD for >12 weeks or a CR or PR, as determined by the investigator according to RECIST v1.1.

As used herein, “overall response rate,” “objective response rate,” and “ORR” refer interchangeably to the sum of CR rate and PR rate. For example, objective response may be defined as a CR or PR per Response Evaluation Criteria in Solid Tumors (RECIST) v.1 .1 , as determined by investigator assessment and confirmed by repeat assessment > 4 weeks after initial documentation. In another example, ORR may be defined as the proportion of patients with CR or PR on two consecutive occasions >4 weeks apart, as determined by the investigator according to RECIST v1 .1 .

As used herein, “progression-free survival” and “PFS” refer to the length of time during and after treatment during which the cancer does not get worse. PFS may include the amount of time patients have experienced a CR or a PR, as well as the amount of time patients have experienced stable disease. For example, PFS may be defined as the time from the first study treatment to the first occurrence of progression or death from any cause, whichever occurs first, per RECIST v.1 .1 as determined by the investigator. In another example, PFS may be defined as the time from study enrollment to the first occurrence of progression or death from any cause, whichever occurs first, per RECIST v.1 .1 as determined by the investigator.

As used herein, “overall survival” and “OS” refer to the length of time from either the date of diagnosis or the start of treatment for a disease (e.g., cancer) that the patient is still alive. For example, OS may be defined as the time from first study treatment to death from any cause.

As used herein, the term “duration of response” and “DOR” refer to a length of time from documentation of a tumor response until disease progression or death from any cause, whichever occurs first. For example, DOR may be defined as the time from the first occurrence of a documented objective response to the time of the first documented disease progression or death from any cause, whichever occurs first, per RECIST v1 .1 as determined by the investigator.

As used herein, the term “chemotherapeutic agent” refers to a compound useful in the treatment of cancer. In some aspects, the chemotherapeutic agent is pemetrexed, paclitaxel, or carboplatin. In some aspects, the chemotherapeutic agent is a combination of paclitaxel and carboplatin. In some aspects, the chemotherapeutic agent is a combination of pemetrexed and carboplatin. In some aspects, the chemotherapeutic agent is nab-paclitaxel. Examples of other chemotherapeutic agents include EGFR inhibitors (including small molecule inhibitors (e.g., erlotinib (TARCEVA®, Genentech/OSI Pharm.); PD 183805 (Cl 1033, 2-propenamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4- morpholinyl)propoxy]-6-quinazolinyl]-, dihydrochloride, Pfizer Inc.); ZD1839, gefitinib (IRESSA®) 4-(3’- Chloro-4’-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6- amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1 - methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim); PKI-166 ((R)-4-[4- [(1 -phenylethyl)amino]-1 H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol); (R)-6-(4-hydroxyphenyl)-4-[(1 - phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine); CL-387785 (N-[4-[(3-bromophenyl)amino]-6- quinazolinyl]-2-butynamide); EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6- quinolinyl]-4-(dimethylamino)-2-butenamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU 5271 ; Pfizer); and dual EGFR/HER2 tyrosine kinase inhibitors such as lapatinib (TYKERB®, GSK572016 or N-[3-chloro-4- [(3 fluorophenyl)methoxy]phenyl]-6[5[[[2methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4- quinazolinamine)); a tyrosine kinase inhibitor (e.g., an EGFR inhibitor; a small molecule HER2 tyrosine kinase inhibitor such as TAK165 (Takeda); CP-724,714, an oral selective inhibitor of the ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual-HER inhibitors such as EKB-569 (available from Wyeth) which preferentially binds EGFR but inhibits both HER2 and EGFR-overexpressing cells; PKI-166 (Novartis); pan-HER inhibitors such as canertinib (CI-1033; Pharmacia); Raf-1 inhibitors such as antisense agent ISIS-5132 (ISIS Pharmaceuticals) which inhibit Raf-1 signaling; non-HER-targeted tyrosine kinase inhibitors such as imatinib mesylate (GLEEVEC®, Glaxo SmithKline); multi-targeted tyrosine kinase inhibitors such as sunitinib (SUTENT®, Pfizer); VEGF receptor tyrosine kinase inhibitors such as vatalanib (PTK787/ZK222584, Novartis/Schering AG); MAPK extracellular regulated kinase I inhibitor CI- 1040 (Pharmacia); quinazolines, such as PD 153035, 4-(3-chloroanilino) quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines, such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines, 4-(phenylamino)-7H-pyrrolo[2,3-d] pyrimidines; curcumin (diferuloyl methane, 4,5- bis (4-fluoroanilino)phthalimide); tyrphostines containing nitrothiophene moieties; PD-0183805 (Warner- Lamber); antisense molecules (e.g., those that bind to HER-encoding nucleic acid); quinoxalines (U.S. Patent No. 5,804,396); tryphostins (U.S. Patent No. 5,804,396); ZD6474 (Astra Zeneca); PTK-787 (Novartis/Schering AG); pan-HER inhibitors such as CI-1033 (Pfizer); Affinitac (ISIS 3521 ; Isis/Lilly); PKI 166 (Novartis); GW2016 (Glaxo SmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis/Schering AG); INC-1 C1 1 (Imclone); and rapamycin (sirolimus, RAPAMUNE®)); proteasome inhibitors such as bortezomib (VELCADE®, Millennium Pharm.); disulfiram; epigallocatechin gallate; salinosporamide A; carfilzomib; 17-AAG (geldanamycin); radicicol; lactate dehydrogenase A (LDH-A); fulvestrant (FASLODEX®, AstraZeneca); letrozole (FEMARA®, Novartis), finasunate (VATALANIB®, Novartis); oxaliplatin (ELOXATIN®, Sanofi); 5-FU (5-fluorouracil); leucovorin; lonafamib (SCH 66336); sorafenib (NEXAVAR®, Bayer Labs); AG1478, alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including topotecan and irinotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); adrenocorticosteroids (including prednisone and prednisolone); cyproterone acetate; 5a-reductases including finasteride and dutasteride); vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat dolastatin; aldesleukin, talc duocarmycin (including the synthetic analogs, KW-2189 and CB1 -TM1 ); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially calicheamicin y1 and calicheamicin w1 ); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, detorubicin, 6-diazo-5-oxo-L- norleucine, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamnol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2- ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2’,2”-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; chloranmbucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; etoposide (VP-16); ifosfamide; mitoxantrone; novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; CPT-11 ; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids, prodrugs, and derivatives of any of the above.

Chemotherapeutic agents also include (i) anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane; Pfizer), formestanie, fadrozole, RIVISOR® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin; buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all transretionic acid, fenretinide, as well as troxacitabine (a 1 ,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in signaling pathways implicated in aberrant cell proliferation, such as, for example, PKC-alpha, Ralf and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME®) and HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®, LEUVECTIN®, and VAXID®; (ix) growth inhibitory agents including vincas (e.g., vincristine and vinblastine), NAVELBINE® (vinorelbine), taxanes (e.g., paclitaxel, nab-paclitaxel, and docetaxel), topoisomerase II inhibitors (e.g., doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin), and DNA alkylating agents (e.g., tamoxigen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, and ara-C); and (x) pharmaceutically acceptable salts, acids, prodrugs, and derivatives of any of the above.

The term “cytotoxic agent” as used herein refers to any agent that is detrimental to cells (e.g., causes cell death, inhibits proliferation, or otherwise hinders a cellular function). Cytotoxic agents include, but are not limited to, radioactive isotopes (e.g., At²¹¹ , 1¹³¹ , I¹²⁵, Y⁹⁰, Re¹⁸⁶, Re¹⁸⁸, Sm¹⁵³, Bi²¹², P³², Pb²¹² and radioactive isotopes of Lu); chemotherapeutic agents; enzymes and fragments thereof such as nucleolytic enzymes; and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof. Exemplary cytotoxic agents can be selected from anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, inhibitors of LDH-A, inhibitors of fatty acid biosynthesis, cell cycle signaling inhibitors, HDAC inhibitors, proteasome inhibitors, and inhibitors of cancer metabolism. In one instance, the cytotoxic agent is a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin). In one instance, the cytotoxic agent is an antagonist of EGFR, e.g., N-(3- ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (e.g., erlotinib). In one instance the cytotoxic agent is a RAF inhibitor, e.g., a BRAF and/or CRAF inhibitor. In one instance the RAF inhibitor is vemurafenib. In one instance, the cytotoxic agent is a PI3K inhibitor.

The term “patient” or “subject” refers to a human patient or subject. For example, the patient or subject may be an adult.

The term “antibody” herein specifically covers monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments so long as they exhibit the desired biological activity. In one instance, the antibody is a full-length monoclonal antibody. In one instance, the antibody is a bispecific antibody.

The term IgG “isotype” or “subclass” as used herein is meant any of the subclasses of immunoglobulins defined by the chemical and antigenic characteristics of their constant regions.

Depending on the amino acid sequences of the constant domains of their heavy chains, antibodies (immunoglobulins) can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG 1 , lgG2, lgG3, lgG4, Ig A1 , and lgA2. The heavy chain constant domains that correspond to the different classes of immunoglobulins are called a, y, e, y, and p, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known and described generally in, for example, Abbas et al. Cellular and Mol. Immunology, 4th ed. (W.B. Saunders, Co., 2000). An antibody may be part of a larger fusion molecule, formed by covalent or non- covalent association of the antibody with one or more other proteins or peptides.

The terms “full-length antibody,” “intact antibody,” and “whole antibody” are used herein interchangeably to refer to an antibody in its substantially intact form, not antibody fragments as defined below. The terms refer to an antibody comprising an Fc region.

The term “Fc region” herein is used to define a C-terminal region of an immunoglobulin heavy chain that contains at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions. In one aspect, a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl-terminus of the heavy chain. However, antibodies produced by host cells may undergo post-translational cleavage of one or more, particularly one or two, amino acids from the C-terminus of the heavy chain. Therefore, an antibody produced by a host cell by expression of a specific nucleic acid molecule encoding a full-length heavy chain may include the full-length heavy chain, or it may include a cleaved variant of the full-length heavy chain. This may be the case where the final two C-terminal amino acids of the heavy chain are glycine (G446) and lysine (K447). Therefore, the C-terminal lysine (Lys447), or the C-terminal glycine (Gly446) and lysine (Lys447), of the Fc region may or may not be present. Amino acid sequences of heavy chains including an Fc region are denoted herein without the C-terminal lysine (Lys447) if not indicated otherwise. In one aspect, a heavy chain including an Fc region as specified herein, comprised in an antibody disclosed herein, comprises an additional C- terminal glycine-lysine dipeptide (G446 and K447). In one aspect, a heavy chain including an Fc region as specified herein, comprised in an antibody disclosed herein, comprises an additional C-terminal glycine residue (G446). In one aspect, a heavy chain including an Fc region as specified herein, comprised in an antibody disclosed herein, comprises an additional C-terminal lysine residue (K447). In one embodiment, the Fc region contains a single amino acid substitution N297A of the heavy chain. Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

A “naked antibody” refers to an antibody that is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or radiolabel. The naked antibody may be present in a pharmaceutical composition.

The term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and/or bind the same epitope, except for possible variant antibodies, e.g., containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies in accordance with the present invention may be made by a variety of techniques, including but not limited to the hybridoma method, recombinant DNA methods, phage-display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci.

The term “hypervariable region” or “HVR” as used herein refers to each of the regions of an antibody variable domain which are hypervariable in sequence and which determine antigen binding specificity, for example “complementarity determining regions” (“CDRs”).

Generally, antibodies comprise six CDRs: three in the VH (CDR-H1 , CDR-H2, CDR-H3), and three in the VL (CDR-L1 , CDR-L2, CDR-L3). Exemplary CDRs herein include:

(a) hypervariable loops occurring at amino acid residues 26-32 (L1 ), 50-52 (L2), 91 -96 (L3), 26-32 (H1 ), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901 -917 (1987));

(b) CDRs occurring at amino acid residues 24-34 (L1 ), 50-56 (L2), 89-97 (L3), 31 -35b (H1 ), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991 )); and

(c) antigen contacts occurring at amino acid residues 27c-36 (L1 ), 46-55 (L2), 89-96 (L3), 30-35b (H1 ), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J. Mol. Biol. 262: 732-745 (1996)).

Unless otherwise indicated, the CDRs are determined according to Kabat et al., supra. One of skill in the art will understand that the CDR designations can also be determined according to Chothia, supra, McCallum, supra, or any other scientifically accepted nomenclature system.

“Framework” or “FR” refers to variable domain residues other than complementary determining regions (CDRs). The FR of a variable domain generally consists of four FR domains: FR1 , FR2, FR3, and FR4. Accordingly, the CDR and FR sequences generally appear in the following sequence in VH (or VL): FR1 -CDR-H1 (CDR-L1 )-FR2- CDR-H2(CDR-L2)-FR3- CDR-H3(CDR-L3)-FR4.

The term “variable domain residue numbering as in Kabat” or “amino acid position numbering as in Kabat,” and variations thereof, refers to the numbering system used for heavy chain variable domains or light chain variable domains of the compilation of antibodies in Kabat et al., supra. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of, or insertion into, a FR or HVR of the variable domain. For example, a heavy chain variable domain may include a single amino acid insert (residue 52a according to Kabat) after residue 52 of H2 and inserted residues (e.g., residues 82a, 82b, and 82c, etc., according to Kabat) after heavy chain FR residue 82. The Kabat numbering of residues may be determined for a given antibody by alignment at regions of homology of the sequence of the antibody with a “standard” Kabat numbered sequence.

The term “monospecific” antibody as used herein denotes an antibody that has one or more binding sites each of which bind to the same epitope of the same antigen. The term “bispecific” antibody as used herein means that the antibody is able to specifically bind to at least two distinct antigens, for example two binding sites each formed by a pair of an antibody heavy chain variable domain (VH) and an antibody light chain variable domain (VL) binding to different antigens or to different epitopes on the same antigen. Such a bispecific antibody is an 1 +1 format. Other bispecific antibody formats are 2+1 formats (comprising two binding sites for a first antigen or epitope and one binding site for a second antigen or epitope) or 2+2 formats (comprising two binding sites for a first antigen or epitope and two binding sites for a second antigen or epitope). Typically, a bispecific antibody comprises two antigen binding sites, each of which is specific for a different antigen. In one instance, the bispecific antibody is a bispecific antibody comprising an Fc domain.

As used herein, a “PD-L1 -positive tumor cell fraction” is the percentage of viable tumor cells showing partial or complete membrane staining (exclusive of cytoplasmic staining) at any intensity relative to all viable tumor cells present in a sample, following staining of the sample in the context of an immunohistochemical (IHC) assay, e.g., an IHC assay staining for PD-L1 using the antibody SP142, SP263, 22C3, or 28-8. Accordingly, a PD-L1 -positive tumor cell fraction may be calculated using the PD- L1 IHC SP142 (Ventana) assay, for example, by the formula PD-L1 -positive tumor cell fraction = (number of PD-L1 -positive tumor cells)/(total number of PD-L1 -positive and PD-L1 negative tumor cells), wherein PD-L1 cytoplasmic staining of tumor cells and all non-tumor cells (e.g., tumor-infiltrating immune cells, normal cells, necrotic cells, and debris) are excluded from evaluation and scoring. It will be appreciated that any given diagnostic PD-L1 antibody may correspond with a particular IHC assay protocol and/or scoring terminology that can be used to derive a PD-L1 -positive tumor cell fraction. For example, a PD- L1 -positive tumor cell fraction can be derived from a tumor cell sample stained with SP263, 22C3, SP142, or 28-8 using OPTIVIEW® detection on Benchmark ULTRA, EnVision Flex on AutostainerLink 48, OPTIVIEW® detection and amplification on Benchmark ULTRA, or EnVision Flex on AutostainerLink 48, respectively.

As used herein, the “Ventana SP142 IHC assay” is conducted according to the Ventana PD-L1 (SP142) Assay package insert (Tucson, AZ: Ventana Medical Systems, Inc.), which is incorporated herein by reference in its entirety.

As used herein, the “Ventana SP263 IHC assay” is conducted according to the Ventana PD-L1 (SP263) Assay package insert (Tucson, AZ: Ventana Medical Systems, Inc.), which is incorporated herein by reference in its entirety.

As used herein, the “pharmDx 22C3 IHC assay” is conducted according to the PD-L1 IHC 22C3 pharmDx package insert (Carpinteria, CA: Dako, Agilent Pathology Solutions), which is incorporated herein by reference in its entirety.

As used herein, the “pharmDx 28-8 IHC assay” is conducted according to the PD-L1 IHC 28-8 pharmDx package insert (Carpinteria, CA: Dako, Agilent Pathology Solutions), which is incorporated herein by reference in its entirety.

The term “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, combination therapy, contraindications and/or warnings concerning the use of such therapeutic products.

As used herein, “in combination with” refers to administration of one treatment modality in addition to another treatment modality, for example, a treatment regimen that includes administration of a bispecific antibody targeting programmed cell death protein 1 (PD-1 ) and lymphocyte activation gene-3 (LAG3) and one or more chemotherapeutic agents (e.g., (a) one or both of pemetrexed and carboplatin, (b) one or both of paclitaxel and carboplatin, or (c) nab-paclitaxel). As such, “in combination with” refers to administration of one treatment modality before, during, or after administration of the other treatment modality to the patient. A drug that is administered “concurrently” with one or more other drugs is administered during a treatment cycle occurring at the same time, during the same treatment cycle, and/or on the same day of treatment as the one or more other drugs, and, optionally, at the same time as the one or more other drugs. For instance, for cancer therapies given every 3 weeks, the concurrently administered drugs may be each administered on day 1 of a 3-week cycle. For dosing regimens comprising dosing cycles of two or more agents with different administration frequencies (e.g., dosing regimens comprising dosing cycles of (a) an agent that is administered every three weeks and (b) an agent that is administered once a week for three weeks, followed by 1 week off), dosing regimens are concurrent if they occur over the same period of time (e.g., the dosing cycles of the two or more agents with different administration frequencies begin on the same day).

As used herein, the term “adverse event” or “AE” refers to any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or procedure that may or may not be considered related to the medical treatment or procedure. Adverse events may be classified by “grade,” as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 or v5.0 (NIH CTCAE). In some aspects, the AE is a low-grade AE, e.g., a Grade 1 or Grade 2 AE. Grade 1 includes AEs that are asymptomatic or have mild symptoms. Grade 2 includes AEs that are moderate and limit age-appropriate instrumental activities of daily living (e.g., preparing meals, shopping for groceries or clothes) and that indicate local or noninvasive intervention. In other instances, the AE is a high-grade AE, e.g., a Grade 3, Grade 4, or Grade 5 AE. In some instances, the AE is a Grade 3 or a Grade 4 AE. Grade 3 includes AEs that are severe or medically significant, but not immediately life-threatening, and that indicate hospitalization or prolongation of hospitalization. Grade 4 includes AEs that have life-threatening consequences and indicate urgent intervention. Grade 5 includes AEs that result in or relate to death.

As used herein, the term “treatment-related AE” refers to an AE that is judged by an investigator to have occurred as a result of a treatment, e.g., a bispecific antibody targeting PD-1 and LAG3 and/or one or more chemotherapeutic agents, e.g., (a) one or both of pemetrexed and carboplatin, (b) one or both of paclitaxel and carboplatin, or (c) nab-paclitaxel.

The term “valent” as used within the current application denotes the presence of a specified number of binding domains in an antigen binding molecule. As such, the terms “bivalent,” “tetravalent,” and “hexavalent” denote the presence of two binding domains, four binding domains, and six binding domains, respectively, in an antigen binding molecule. The bispecific antibodies according to the invention are at least “bivalent” and may be “trivalent” or “multivalent” (e.g., “tetravalent” or “hexavalent”). In a particular aspect, the antibodies of the present invention have two or more binding sites and are bispecific. That is, the antibodies may be bispecific even in cases where there are more than two binding sites (i.e. , that the antibody is trivalent or multivalent).

An "antibody fragment" refers to a molecule other than an intact antibody that comprises a portion of an intact antibody that binds the antigen to which the intact antibody binds. Examples of antibody fragments include but are not limited to Fv, Fab, Fab', Fab’-SH, F(ab')2; diabodies, triabodies, tetrabodies, cross-Fab fragments; linear antibodies; single-chain antibody molecules (e.g., scFv); multispecific antibodies formed from antibody fragments and single domain antibodies. For a review of certain antibody fragments, see Hudson et al., Nat Med 9, 129-134 (2003). For a review of scFv fragments, see e.g., Pluckthun, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer- Verlag, New York, pp. 269-315 (1994); see also WO 93/16185; and U.S. Patent Nos. 5,571 ,894 and 5,587,458. For discussion of Fab and F(ab')2 fragments comprising salvage receptor binding epitope residues and having increased in vivo half-life, see U.S. Patent No. 5,869,046. Diabodies are antibody fragments with two antigen-binding domains that may be bivalent or bispecific, see, for example, EP 404,097; WO 1993/01161 ; Hudson et al., Nat Med 9, 129-134 (2003); and Hollinger et al., Proc Natl Acad Sci USA 90, 6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al., Nat Med 9, 129-134 (2003). Single-domain antibodies are antibody fragments comprising all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody. In certain embodiments, a single-domain antibody is a human single-domain antibody (Domantis, Inc., Waltham, MA; see e.g., U.S. Patent No. 6,248,516 B1 ). In addition, antibody fragments comprise single chain polypeptides having the characteristics of a VH domain, namely being able to assemble together with a VL domain, or of a VL domain, namely being able to assemble together with a VH domain to a functional antigen binding site and thereby providing the antigen binding property of full- length antibodies. Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as production by recombinant host cells (e.g., E. coli or phage), as described herein.

Papain digestion of intact antibodies produces two identical antigen-binding fragments, called “Fab” fragments containing each the heavy- and light-chain variable domains and also the constant domain of the light chain and the first constant domain (CH1 ) of the heavy chain. As used herein, Thus, the term “Fab fragment” refers to an antibody fragment comprising a light chain fragment comprising a VL domain and a constant domain of a light chain (CL), and a VH domain and a first constant domain (CH1 ) of a heavy chain. Fab’ fragments differ from Fab fragments by the addition of a few residues at the carboxy terminus of the heavy chain CH1 domain including one or more cysteins from the antibody hinge region. Fab’-SH are Fab’ fragments wherein the cysteine residue(s) of the constant domains bear a free thiol group. Pepsin treatment yields an F(ab')2 fragment that has two antigen-combining sites (two Fab fragments) and a part of the Fc region.

The term “cross-Fab fragment” or “xFab fragment” or “crossover Fab fragment” refers to a Fab fragment, wherein either the variable regions or the constant regions of the heavy and light chain are exchanged. Two different chain compositions of a crossover Fab molecule are possible and comprised in the bispecific antibodies of the invention: On the one hand, the variable regions of the Fab heavy and light chain are exchanged, i.e., the crossover Fab molecule comprises a peptide chain composed of the light chain variable region (VL) and the heavy chain constant region (CH1 ), and a peptide chain composed of the heavy chain variable region (VH) and the light chain constant region (CL). This crossover Fab molecule is also referred to as CrossFab <VLVH). On the other hand, when the constant regions of the Fab heavy and light chain are exchanged, the crossover Fab molecule comprises a peptide chain composed of the heavy chain variable region (VH) and the light chain constant region (CL), and a peptide chain composed of the light chain variable region (VL) and the heavy chain constant region (CH1 ). This crossover Fab molecule is also referred to as CrossFab <CLCHI).

A “single chain Fab fragment” or “scFab” is a polypeptide consisting of an antibody heavy chain variable domain (VH), an antibody constant domain 1 (CH1 ), an antibody light chain variable domain (VL), an antibody light chain constant domain (CL) and a linker, wherein said antibody domains and said linker have one of the following orders in N-terminal to C-terminal direction: a) VH-CH1 -linker-VL-CL, b) VL-CL-linker-VH-CH1 , c) VH-CL-linker-VL-CH1 or d) VL-CH1 -linker-VH-CL; and wherein said linker is a polypeptide of at least 30 amino acids, preferably between 32 and 50 amino acids. Said single chain Fab fragments are stabilized via the natural disulfide bond between the CL domain and the CH1 domain. In addition, these single chain Fab molecules might be further stabilized by generation of interchain disulfide bonds via insertion of cysteine residues (e.g., position 44 in the variable heavy chain and position 100 in the variable light chain according to Kabat numbering).

A “crossover single chain Fab fragment” or “x-scFab” is a is a polypeptide consisting of an antibody heavy chain variable domain (VH), an antibody constant domain 1 (CH1 ), an antibody light chain variable domain (VL), an antibody light chain constant domain (CL) and a linker, wherein said antibody domains and said linker have one of the following orders in N-terminal to C-terminal direction: a) VH-CL-linker-VL-CH1 and b) VL-CH1 -linker-VH-CL; wherein VH and VL form together an antigen-binding domain which binds specifically to an antigen and wherein said linker is a polypeptide of at least 30 amino acids. In addition, these x-scFab molecules might be further stabilized by generation of interchain disulfide bonds via insertion of cysteine residues (e.g., position 44 in the variable heavy chain and position 100 in the variable light chain according to Kabat numbering).

A “single-chain variable fragment (scFv)” is a fusion protein of the variable regions of the heavy (VH) and light chains (VL) of an antibody, connected with a short linker peptide of ten to about 25 amino acids. The linker is usually rich in glycine for flexibility, as well as serine or threonine for solubility, and can either connect the N-terminus of the VH with the C-terminus of the VL, or vice versa. This protein retains the specificity of the original antibody, despite removal of the constant regions and the introduction of the linker. scFv antibodies are, e.g., described in Houston, J.S., Methods in Enzymol. 203 (1991 ) 46-96). In addition, antibody fragments comprise single chain polypeptides having the characteristics of a VH domain, namely being able to assemble together with a VL domain, or of a VL domain, namely being able to assemble together with a VH domain to a functional antigen binding site and thereby providing the antigen binding property of full-length antibodies.

A single-domain antibody is an antibody fragment consisting of a single monomeric variable antibody domain. The first single domains were derived from the variable domain of the antibody heavy chain from camelids (nanobodies or VHH fragments). Furthermore, the term single-domain antibody includes an autonomous human heavy chain variable domain (aVH) or VNAR fragments derived from sharks. Fibronectin is a scaffold which can be engineered to bind to antigen. Adnectins consists of a backbone of the natural amino acid sequence of the 10th domain of the 15 repeating units of human fibronectin type III (FN3). Three loops at one end of the p-sandwich can be engineered to enable an Adnectin to specifically recognize a therapeutic target of interest. For further details see Protein Eng. Des. Sei. 18, 435- 444 (2005), US20080139791 , W02005056764 and US6818418B1. Peptide aptamers are combinatorial recognition molecules that consist of a constant scaffold protein, typically thioredoxin (TrxA) which contains a constrained variable peptide loop inserted at the active site. For further details see Expert Opin. Biol. Ther. 5, 783-797 (2005). Microbodies are derived from naturally occurring microproteins of 25-50 amino acids in length which contain 3-4 cysteine bridges - examples of microproteins include KalataBI and conotoxin and knottins. The microproteins have a loop which can beengineered to include upto 25 amino acids without affecting the overall fold of the microprotein. For further details of engineered knottin domains, see W02008098796.

The term “a bispecific antibody comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3,” “a bispecific antibody that specifically binds PD-1 and LAG3,” “bispecific antigen binding molecule specific for PD-1 and LAG3” or an “anti-PD-1/anti-LAG3 antibody” are used interchangeably herein and refer to a bispecific antibody that is capable of binding PD-1 and LAG3 with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting PD-1 and LAG3. In some aspects, the bispecific antibody targeting PD-1 and LAG3 comprises (a) a first antigen-binding domain that specifically binds to PD-1 comprising a heavy chain variable (VH) domain comprising (i) an HVR-H1 sequence comprising the amino acid sequence of SEQ ID NO: 1 , (ii) an HVR-H2 sequence comprising the amino acid sequence GGR, and (iii) an HVR-H3 sequence comprising an amino acid sequence of SEQ ID NO: 2; and a light chain variable (VL) domain comprising (i) an HVR-L1 sequence comprising the amino acid sequence of SEQ ID NO: 3; (ii) an HVR-L2 sequence comprising the amino acid sequence RSS, and (iii) an HVR-L3 sequence comprising the amino acid sequence of SEQ ID NO: 4 and (b) a second antigen-binding domain that specifically binds to LAG3 comprising a VH domain comprising (i) an HVR-H1 sequence comprising the amino acid sequence of SEQ ID NO: 7, (ii) an HVR-H2 sequence comprising the amino acid sequence of SEQ ID NO: 8, and (iii) an HVR-H3 sequence comprising an amino acid sequence of SEQ ID NO: 9; and a VL domain comprising (i) an HVR-L1 sequence comprising the amino acid sequence of SEQ ID NO: 10, (ii) an HVR-L2 sequence comprising the amino acid sequence of SEQ ID NO: 11 , and (iii) an HVR-L3 sequence comprising the amino acid sequence of SEQ ID NO: 12. In some aspects, the first antigen-binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 5 and a VL domain comprising the amino acid sequence of SEQ ID NO: 6, and the second antigen-binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 13 and a VL domain comprising the amino acid sequence of SEQ ID NO: 14. In some aspects, the bispecific antibody that specifically binds PD-1 and LAG3 is RO7247669. The RO7247669 antibody was first described in WO 2018/185043, which is hereby incorporated by reference in its entirety.

RO7247669 is a novel, fragment crystallizable (Fc)-silent lgG1 -based bispecific antibody (BsAb) in a 1 + 1 format, that incorporates monovalent binding to the checkpoint receptors, PD-1 and lymphocyte activation gene 3 (LAG3). Use of a natural IgG-like monovalent heterodimeric IgG 1 format allows the antibody to simultaneously bind to PD-1 and LAG3. The RO7247669 BsAb is engineered to preferentially bind to T-cells that co-express both PD-1 and LAG3, or to a lesser extent either PD-1 or LAG3 alone. Monovalent binding to LAG3 reduces internalization of the antibody (Ab) upon binding to the T-cell surface, and the retention time of RO7247669 on the T-cell surface is higher when simultaneously bound to PD-1 and LAG3. PGLALA mutations have been introduced into the lgG1 - based Fc region of RO7247669 to avoid drug-shaving and thus tumor-associated macrophage resistance mechanisms that have been observed with lgG4-based antibodies such as KEYTRUDA® (pembrolizumab) and OPDIVO® (nivolumab) (Arlauckas et al., Sci Transl Med, 9: eaal3604, 2017; Shen et al., Eur J Pharm Sci, 157:105629, 2021 ).

The term “PD-1 ,” also known as Programmed cell death protein 1 , is a type I membrane protein of 288 amino acids that was first described in 1992 (Ishida et al., EMBO J., 11 (1992), 3887-3895). PD-1 is a member of the extended CD28/CTLA-4 family of T cell regulators and has two ligands, PD-L1 (B7- H1 , CD274) and PD-L2 (B7-DC, CD273). The protein's structure includes an extracellular IgV domain followed by a transmembrane region and an intracellular tail. The intracellular tail contains two phosphorylation sites located in an immunoreceptor tyrosine-based inhibitory motif and an immunoreceptor tyrosine-based switch motif, which suggests that PD-1 negatively regulates TCR signals. This is consistent with binding of SHP-1 and SHP-2 phosphatases to the cytoplasmic tail of PD-1 upon ligand binding. While PD-1 is not expressed on naive T cells, it is upregulated following T cell receptor (TCR)-mediated activation and is observed on both activated and exhausted T cells (Agata et al., Int. Immunology 8 (1996), 765-772). These exhausted T-cells have a dysfunctional phenotype and are unable to respond appropriately. Although PD-1 has a relatively wide expression pattern its most important role is likely as a coinhibitory receptor on T cells (Chinai et al, Trends in Pharmacological Sciences 36 (2015), 587-595). Current therapeutic approaches thus focus on blocking the interaction of PD-1 with its ligands to enhance T cell response. The terms “Programmed Death 1 ,” “Programmed Cell Death 1 ,” “Protein PD-1 ,” “PD-1 ,” PD1 ,” “PDCD1 ,” “hPD-1 ” and “hPD-1 ” can be used interchangeably, and include variants, isoforms, species homologs of human PD-1 , and analogs having at least one common epitope with PD-1 . The amino acid sequence of human PD-1 is shown in UniProt (www.uniprot.org) accession no. Q15116 (SEQ ID NO: 19).

Encouraging clinical data in the field of tumor immunotherapy have demonstrated that therapies focused on enhancing T-cell responses against cancer can result in a significant survival benefit in patients with advanced malignancies (Hodi et al., N Engl J Med, 363: 711 -723, 2010; Kantoff et al., N Engl J Med, 363: 411 -422, 2010; Chen et al., Clin Cancer Res, 18: 6580-6587, 2012).

The “PD-1/PD-L1” pathway serves as an immune checkpoint to temporarily dampen immune responses in states of chronic antigen stimulation, such as chronic infection or cancer. PD-1 is an inhibitory receptor that is expressed on activated and exhausted T cells, including tumor infiltrating CD8⁺ T cells that recognize mutated tumor antigens (neo-antigens). Binding of PD-L1 to PD-1 inhibits T-cell proliferation, activation, cytokine production, and cytolytic activity, leading to a functionally inactivated and exhausted T-cell state (Butte et al., Immunity, 27: 111 -122, 2007; Yang et al., J. Immunol., 187: 1113- 1119, 2011 ). Therapeutic targeting of the PD-1/PD-L1 pathway to enhance anti-tumor T-cell responses has been clinically validated across multiple solid tumors, including TNBC, when given both as a singleagent treatment and in combination with chemotherapy and other targeted agents.

The terms “LAG3” or “Lag-3” or “Lymphocyte activation gene-3” or “CD223” as used herein refer to any native LAG3 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. The term encompasses “full-length,” unprocessed LAG3 as well as any form of LAG3 resulting from processing in the cell. The term also encompasses naturally occurring variants of LAG3, e.g., splice variants or allelic variants. In one preferred embodiment the term “LAG3” refers to human LAG3. The amino acid sequence of an exemplary processed (without signal sequences) LAG3 is shown in SEQ ID NO: 20. The amino acid sequence of an exemplary Extracellular Domain (ECD) LAG3 is shown in SEQ ID NO: 21 .

LAG3 is an immune checkpoint protein involved in the regulation of anti-tumor immunity and chronic infection. LAG3 is expressed on activated T cells, B cells, natural killer cells, and a subset of tolerogenic plasmacytoid dendritic cells, and constitutively on T-regulatory cells (Huard et al., Immunogenetics, 39: 213-217, 1994). Structurally similar to CD4, LAG3 is a member of the Ig superfamily and binds to major histocompatibility complex class II (MHC-II). The interaction of LAG3 with MHC-II inhibits T-cell proliferation, activation, cytolytic function, and proinflammatory cytokine production (Goldberg and Drake, Curr Top Microbiol Immunol, 344: 269-278, 201 1 ).

Expression of LAG3 has been reported across various tumor types, including non-small cell lung cancer (NSCLC), hepatocellular carcinoma, breast cancer, ovarian cancer, melanoma, renal cell carcinoma, and prostate cancer, and is associated with poor prognosis (Matsuzaki et al., Proc Natl Acad Sci U.S.A., 107: 7875-7880, 2010; Baitsch et al., J Clin Invest, 121 : 2350-2360, 201 1 ; Thommen et al., Cancer Immunol Res, 3: 1344-1355, 2015; He et al., Cancer Sci, 107: 1 193-1 197, 2016; Norstrbm et al., Oncotarget, 7: 23581 -23593, 2016). Clinical evaluation of anti-LAG3 agents, given as a single agent and in combination with other checkpoint inhibitors (CPIs), is ongoing in several early-phase studies in patients with advanced solid tumors (Long et al., Genes Cancer, 9: 176-189, 2018). Preliminary data demonstrate that anti-LAG3 therapy is well tolerated as a single agent and in combination with anti-PD-1 therapies, and the safety profiles were consistent with those of other CPI treatments (Ascierto et al., Ann Oncol, 28 (Supplement 5): mdx440.01 1 , 2017; Hong et al., J Clin Oncol, 36: 3012, 2018; Stratton et al., SITC Abstract P325, 2018). Thus, therapeutic targeting of LAG3 represents an attractive strategy for the treatment of patients with NSCLC or TNBC.

The terms “anti-LAG3 antibody” and “an antibody that binds to LAG3” refer to an antibody that is capable of binding LAG3 with sufficient affinity such that the antibody is useful as a diagnostic and/or therapeutic agent in targeting LAG3. In one aspect, the extent of binding of an anti-LAG3 antibody to an unrelated, non-LAG3 protein is less than about 10% of the binding of the antibody to LAG3 as measured, e.g., by a radioimmunoassay (RIA). In certain embodiments, an antibody that binds to LAG3 has a dissociation constant (KD) of < 1 uM, < 100 nM, < 10 nM, < 1 nM, < 0.1 nM, < 0.01 nM, or < 0.001 nM (e.g., 10^-8 M or less, e.g., from 10^-8 M to 10^-13 M, e.g., from 10^-9 M to 10^-13 M). In certain aspects, an anti- LAG3 antibody binds to an epitope of LAG3 that is conserved among LAG3 from different species. In one preferred embodiment, an “anti-LAG3 antibody,” “an antibody that specifically binds to human LAG3,” and “an antibody that binds to human LAG3” refers to an antibody specifically binding to the human LAG3 antigen or its Extracellular Domain (ECD) with a binding affinity of a Ko-value of 1 .0 x 10^-8 mol/l or lower, in one embodiment of a Ko-value of 1 .0 x 10^-9 mol/l or lower, in one embodiment of a Ko-value of 1 .0 x 10^-9 mol/l to 1 .0 x 10^-13 mol/l. In this context the binding affinity is determined with a standard binding assay, such as surface plasmon resonance technique (BIAcore®, GE-Healthcare Uppsala, Sweden) e.g., using the LAG3 extracellular domain. The term “anti-LAG3 antibody” also encompasses bispecific antibodies that are capable of binding LAG3 and a second antigen.

The “knob-into-hole” technology is described e.g., in US 5,731 ,168; US 7,695,936; Ridgway et al., Prot Eng 9, 617-621 (1996) and Carter, J Immunol Meth 248, 7-15 (2001 ). Generally, the method involves introducing a protuberance (“knob”) at the interface of a first polypeptide and a corresponding cavity (“hole”) in the interface of a second polypeptide, such that the protuberance can be positioned in the cavity so as to promote heterodimer formation and hinder homodimer formation. Protuberances are constructed by replacing small amino acid side chains from the interface of the first polypeptide with larger side chains (e.g., tyrosine or tryptophan). Compensatory cavities of identical or similar size to the protuberances are created in the interface of the second polypeptide by replacing large amino acid side chains with smaller ones (e.g., alanine or threonine). The protuberance and cavity can be made by altering the nucleic acid encoding the polypeptides, e.g., by site-specific mutagenesis, or by peptide synthesis. In a specific embodiment a knob modification comprises the amino acid substitution T366W in one of the two subunits of the Fc domain, and the hole modification comprises the amino acid substitutions T366S, L368A and Y407V in the other one of the two subunits of the Fc domain. In a further specific embodiment, the subunit of the Fc domain comprising the knob modification additionally comprises the amino acid substitution S354C, and the subunit of the Fc domain comprising the hole modification additionally comprises the amino acid substitution Y349C. Introduction of these two cysteine residues results in the formation of a disulfide bridge between the two subunits of the Fc region, thus further stabilizing the dimer (Carter, J Immunol Methods 248, 7-15 (2001 )).

The term “effector functions” refers to those biological activities attributable to the Fc region of an antibody, which vary with the antibody isotype. Examples of antibody effector functions include: C1 q binding and complement dependent cytotoxicity (CDC), Fc receptor binding, antibody-dependent cell- mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), cytokine secretion, immune complex-mediated antigen uptake by antigen presenting cells, down regulation of cell surface receptors (e.g., B cell receptor), and B cell activation.

An “activating Fc receptor” is an Fc receptor that following engagement by an Fc region of an antibody elicits signaling events that stimulate the receptor-bearing cell to perform effector functions. Activating Fc receptors include FcyRllla (CD16a), FcyRI (CD64), FcyRlla (CD32), and FcaRI (CD89). A particular activating Fc receptor is human FcyRllla (see UniProt accession no. P08637, version 141 ).

The term “peptide linker” refers to a peptide comprising one or more amino acids, typically about 2 to 20 amino acids. Peptide linkers are known in the art or are described herein. Suitable, non- immunogenic linker peptides are, for example, (G4S)n, (SG4)n or G4(SG4)n peptide linkers, wherein “n” is generally a number between 1 and 10, typically between 2 and 4, in particular 2, i.e. the peptides selected from the group consisting of GGGGS (SEQ ID NO: 22) GGGGSGGGGS (SEQ ID NO: 23), SGGGGSGGGG (SEQ ID NO: 24) and GGGGSGGGGSGGGG (SEQ ID NO: 25), but also include the sequences GSPGSSSSGS (SEQ ID NO: 26), (G4S)₃ (SEQ ID NO: 27), (G4S)₄ (SEQ ID NO: 28), GSGSGSGS (SEQ ID NO: 29), GSGSGNGS (SEQ ID NO: 30), GGSGSGSG (SEQ ID NO: 31 ), GGSGSG (SEQ ID NO: 32), GGSG (SEQ ID NO: 33), GGSGNGSG (SEQ ID NO: 34), GGNGSGSG (SEQ ID NO: 35) and GGNGSG (SEQ ID NO: 36). Peptide linkers of particular interest are (G4S) (SEQ ID NO: 22), (G₄S)₂ or GGGGSGGGGS (SEQ ID NO: 23), (G4S)₃ (SEQ ID NO: 27) and (G₄S)₄ (SEQ ID NO: 29), more particularly (G₄S)₂ (SEQ ID NO: 23) or GGGGSGGGGS (SEQ ID NO: 23).

By “fused to” or “connected to” is meant that the components (e.g., an antigen-binding domain and a Fc domain) are linked by peptide bonds, either directly or via one or more peptide linkers.

II. Therapeutic Methods and Compositions for Non-Small Cell Lung Cancer or TripleNegative Breast Cancer

A. Non-Squamous NSCLC

In one aspect, the disclosure provides a method for treating a subject having a non-squamous non-small cell lung cancer (NSCLC) (e.g., a Stage IIIB/IIIC or Stage IV non-squamous NSCLC), the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of (a) a bispecific antibody targeting PD-1 and LAG3 comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3; (b) pemetrexed; and (c) carboplatin.

In another aspect, the disclosure provides a bispecific antibody targeting PD-1 and LAG3 for use in a method of treating a subject having a NSCLC (e.g., a Stage IIIB/IIIC or Stage IV non-squamous NSCLC), wherein the method comprises a dosing regimen comprising a bispecific antibody targeting PD- 1 and LAG3, pemetrexed, and carboplatin, wherein the bispecific antibody comprises a first antigenbinding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, and wherein the dosing regimen comprises administering to the subject one or more dosing cycles of (a) the bispecific antibody; (b) pemetrexed; and (c) carboplatin.

Exemplary bispecific antibodies targeting PD-1 and LAG3 are provided in Section IV, below. A particular example for a bispecific antibody targeting PD-1 and LAG3 is PD1 -LAG3 as defined herein. In some aspects, the method comprises administering the bispecific antibody (e.g., a bispecific antibody targeting PD-1 and LAG3 as provided in Section IV) at a fixed dose of 600 mg every three weeks (Q3W). In some aspects, the length of each of the one or more dosing cycles of the bispecific antibody is 21 days, and the method comprises administering (e.g., intravenously administering) to the subject the bispecific antibody on Day 1 of each of the one or more dosing cycles. For example, the bispecific antibody may be administered by intravenous infusion over about 60 minutes or over about 30 minutes. In some aspects, the bispecific antibody is administered by intravenous infusion over a longer duration in a first cycle and over a shorter duration in a second or further dosing cycle: for example, in some aspects, the bispecific antibody is administered over 60 (± 15) minutes (e.g., over about 60 minutes) in a first dosing cycle and is administered over 30 (± 10) minutes (e.g., over about 30 minutes) in the one or more additional dosing cycles.

In some aspects, the method comprises administering (e.g., intravenously administering) to the subject the pemetrexed at a dose of 500 mg/m² every three weeks.

In some aspects, the method comprises administering (e.g., intravenously administering) to the subject the carboplatin at a targeted area under the concentration-time curve (AUC) of 5 mg/mL • min every three weeks.

In some aspects, the length of each of the one or more dosing cycles is 21 days, and the method comprises administering (e.g., intravenously administering) to the subject the bispecific antibody, the pemetrexed, and the carboplatin on Day 1 of each of the one or more dosing cycles.

On days on which the bispecific antibody, the pemetrexed, and the carboplatin are administered on the same day, the method may comprise (a) administering to the subject the bispecific antibody first, the pemetrexed second, and the carboplatin third or (b) administering to the subject the pemetrexed first, the carboplatin second, and the bispecific antibody third. Alternatively, the method may comprise (c) administering to the subject the bispecific antibody first, the carboplatin second, and the pemetrexed third; (d) administering to the subject the carboplatin first, the pemetrexed second, and the bispecific antibody third; (e) administering to the subject the carboplatin first, the bispecific antibody second, and the pemetrexed third; or (f) administering to the subject the pemetrexed first, the bispecific antibody second, and the carboplatin third. In some aspects, the dosing regimen comprises at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 15, 14, 15, 16, 17, 18, 19, 20, or more than 20 dosing cycles of the bispecific antibody, the pemetrexed, and the carboplatin. In some aspects, the dosing regimen comprises four dosing cycles of the bispecific antibody, the pemetrexed, and the carboplatin.

In some aspects, the dosing regimen comprises one or more dosing cycles (e.g., 4 dosing cycles) of the bispecific antibody, the pemetrexed, and the carboplatin and further comprises one or more additional dosing cycles of (a) the bispecific antibody and (b) pemetrexed (e.g., one or more additional dosing cycles comprising administration of the bispecific antibody and pemetrexed as described above and not comprising administration of carboplatin). For example , in some aspects, the dosing regimen comprises at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 15, 14, 15, 16, 17, 18, 19, 20, or more than 20 additional dosing cycles of (a) the bispecific antibody and (b) pemetrexed (e.g., comprises at least 5 or at least 10 additional dosing cycles of (a) the bispecific antibody and (b) pemetrexed).

For example, in one aspect, the disclosure provides a method for treating a subject having a non- squamous Stage IIIB/IIIC NSCLC or a Stage IV NSCLC, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of (a) a bispecific antibody targeting PD- 1 and LAG3 comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, wherein the method comprises administering to the subject the bispecific antibody at a fixed dose of 600 mg every three weeks, and wherein the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 15, a first light chain comprising the amino acid sequence of SEQ ID NO: 16, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 17, and a second light chain comprising the amino acid sequence of SEQ ID NO: 18; (b) pemetrexed, wherein the method comprises administering to the subject the pemetrexed at a dose of 500 mg/m² every three weeks; and (c) carboplatin, wherein the method comprises administering to the subject the carboplatin at a targeted area under the concentration-time curve (AUC) of 5 mg/mL • min every three weeks.

In one aspect, the disclosure provides a bispecific antibody targeting PD-1 and LAG3 for use in a method of treating a subject having a non-squamous Stage IIIB/IIIC NSCLC or a Stage IV NSCLC, wherein the method comprises a dosing regimen comprising a bispecific antibody targeting PD-1 and LAG3, pemetrexed, and carboplatin, wherein the bispecific antibody comprises a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, and wherein the dosing regimen comprises administering to the subject one or more dosing cycles of (a) the bispecific antibody, wherein the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 15, a first light chain comprising the amino acid sequence of SEQ ID NO: 16, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 17, and a second light chain comprising the amino acid sequence of SEQ ID NO: 18; (b) pemetrexed, wherein the method comprises administering to the subject the pemetrexed at a dose of 500 mg/m² every three weeks; and (c) carboplatin, wherein the method comprises administering to the subject the carboplatin at a targeted area under the concentration-time curve (AUC) of 5 mg/mL • min every three weeks.

In some aspects, the non-squamous NSCLC is a locally advanced unresectable or metastatic non-squamous NSCLC, e.g., is (a) a Stage IIIB/IIIC non-squamous NSCLC; or (b) a Stage IV non- squamous NSCLC. In some aspects, the non-squamous NSCLC (e.g., locally advanced unresectable or metastatic non-squamous NSCLC, e.g., Stage IIIB/IIIC or Stage IV non-squamous NSCLC) is first-line (1 L), e.g., the subject has not previously received a systemic anti-cancer therapy for locally advanced, unresectable or metastatic NSCLC. In some aspects, the subject has not received prior systemic treatment for metastatic NSCLC.

In some aspects, the non-squamous NSCLC is a PD-L1 -positive NSCLC. Exemplary methods for assessing PD-L1 expression level are provided, e.g., in Section III, below. In some aspects, a tumor sample from the NSCLC of the subject has a PD-L1 tumor proportion score (TPS) or a PD-L1 expression level on tumor cells (TCs) of <1%. In some aspects, a tumor sample from the NSCLC of the subject has a PD-L1 TPS or a PD-L1 expression level on TCs of between 1% and 49%. In some aspects, a tumor sample from the NSCLC of the subject has a PD-L1 TPS or a PD-L1 expression level on TCs of >50%. In other aspects, the non-squamous NSCLC is a PD-L1 -negative NSCLC.

In some aspects, the method results in an increase in progression-free survival (PFS) (e.g., an increase of at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, or more than 100%, e.g., an increase of 1 -5%, 5-10%, 10-15%, 15- 20%, 20-25%, 25-30%, 30-35%, 35-40%, 40-45%, 45-50%, 50-55%, 55-60%, 60-65%, 65-70%, 70-75%, 75-80%, 80-85%, 85-90%, 90-95%, 95-100%, or more than 100%) as compared to a reference PFS. In some aspects, the reference PFS is a PFS of a population of subjects who have received a control therapy.

In some aspects, the method results in an increase in objective response rate (ORR) (e.g., an increase of at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, or more than 100%, e.g., an increase of 1 -5%, 5-10%, 10-15%, 15- 20%, 20-25%, 25-30%, 30-35%, 35-40%, 40-45%, 45-50%, 50-55%, 55-60%, 60-65%, 65-70%, 70-75%, 75-80%, 80-85%, 85-90%, 90-95%, 95-100%, or more than 100%) in a population of subjects treated according to the method as compared to a reference ORR. In some aspects, the reference ORR is an ORR of a population of subjects who have received a control therapy.

In some aspects, the method results in an increase in overall survival (OS) (e.g., an increase of at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, or more than 100%, e.g., an increase of 1 -5%, 5-10%, 10-15%, 15-20%, 20- 25%, 25-30%, 30-35%, 35-40%, 40-45%, 45-50%, 50-55%, 55-60%, 60-65%, 65-70%, 70-75%, 75-80%, 80-85%, 85-90%, 90-95%, 95-100%, or more than 100%) as compared to a reference OS. In some aspects, the reference OS is an OS of a population of subjects who have received a control therapy.

In some aspects, the method results in an increase in duration of response (DOR) (e.g., an increase of at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, or more than 100%, e.g., an increase of 1 -5%, 5-10%, 10-15%, 15- 20%, 20-25%, 25-30%, 30-35%, 35-40%, 40-45%, 45-50%, 50-55%, 55-60%, 60-65%, 65-70%, 70-75%, 75-80%, 80-85%, 85-90%, 90-95%, 95-100%, or more than 100%) as compared to a reference DOR. In some aspects, the reference DOR is a DOR of a population of subjects who have received a control therapy.

In some aspects, the subject has a non-squamous NSCLC, and the control therapy comprises pembrolizumab, pemetrexed, and carboplatin and does not comprise the bispecific antibody. For example, in some aspects, the control therapy consists of pembrolizumab, pemetrexed, and carboplatin.

In some aspects, the subject is a human.

B. Squamous NSCLC

In another aspect, the disclosure provides a method for treating a subject having a squamous non-small cell lung cancer (NSCLC) (e.g., a Stage IIIB/IIIC or Stage IV squamous NSCLC), the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of (a) a bispecific antibody targeting PD-1 and LAG3 comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3; (b) paclitaxel; and (c) carboplatin.

In one aspect, the disclosure provides a bispecific antibody targeting PD-1 and LAG3 for use in a method of treating a subject having a squamous NSCLC (e.g., a Stage IIIB/IIIC or Stage IV squamous NSCLC), wherein the method comprises a dosing regimen comprising a bispecific antibody targeting PD- 1 and LAG3, paclitaxel, and carboplatin, wherein the bispecific antibody comprises a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, and wherein the dosing regimen comprises administering to the subject one or more dosing cycles of (a) the bispecific antibody; (b) paclitaxel; and (c) carboplatin.

In some aspects, the method comprises administering (e.g., intravenously administering) to the subject the paclitaxel at a dose of 200 mg/m² every three weeks. In some aspects, the subject is premedicated (e.g., is premedicated with an oral or IV steroid and antihistamines prior to administration of the paclitaxel).

In some aspects, the method comprises administering (e.g., intravenously administering) to the subject the carboplatin at a targeted AUC of 5 mg/mL • min every three weeks.

In some aspects, the length of each of the one or more dosing cycles is 21 days, and wherein the method comprises administering to the subject the bispecific antibody, the paclitaxel, and the carboplatin on Day 1 of each of the one or more dosing cycles.

On days on which the bispecific antibody, the paclitaxel, and the carboplatin are administered on the same day, the method may comprise (a) administering to the subject the bispecific antibody first, the paclitaxel second, and the carboplatin third or (b) administering to the subject the paclitaxel first, the carboplatin second, and the bispecific antibody third. Alternatively, the method may comprise (c) administering to the subject the bispecific antibody first, the carboplatin second, and the paclitaxel third; (d) administering to the subject the carboplatin first, the paclitaxel second, and the bispecific antibody third; (e) administering to the subject the carboplatin first, the bispecific antibody second, and the paclitaxel third; or (f) administering to the subject the paclitaxel first, the bispecific antibody second, and the carboplatin third.

In some aspects, the dosing regimen comprises at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 15, 14, 15, 16, 17, 18, 19, 20, or more than 20 dosing cycles of the bispecific antibody, the paclitaxel, and the carboplatin. In some aspects, the dosing regimen comprises four dosing cycles of the bispecific antibody, the paclitaxel, and the carboplatin.

In some aspects, the dosing regimen comprises one or more dosing cycles (e.g., 4 dosing cycles) of the bispecific antibody, the paclitaxel, and the carboplatin and further comprises one or more additional dosing cycles of the bispecific antibody (e.g., one or more additional dosing cycles comprising administration of the bispecific antibody as described above and not comprising administration of paclitaxel or carboplatin). For example , in some aspects, the dosing regimen comprises at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 15, 14, 15, 16, 17, 18, 19, 20, or more than 20 additional dosing cycles of the bispecific antibody (e.g., comprises at least 5 or at least 10 additional dosing cycles of (a) the bispecific antibody.

For example, in one aspect, the disclosure provides a method for treating a subject having a squamous Stage IIIB/IIIC NSCLC or a Stage IV NSCLC, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of (a) a bispecific antibody targeting PD- 1 and LAG3 comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, wherein the method comprises administering to the subject the bispecific antibody at a fixed dose of 600 mg every three weeks, and wherein the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 15, a first light chain comprising the amino acid sequence of SEQ ID NO: 16, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 17, and a second light chain comprising the amino acid sequence of SEQ ID NO: 18; (b) paclitaxel, wherein the method comprises administering to the subject the paclitaxel at a dose of 200 mg/m² every three weeks; and (c) carboplatin, wherein the method comprises administering to the subject the carboplatin at a targeted AUC of 5 mg/mL • min every three weeks.

In one aspect, the disclosure provides a bispecific antibody targeting PD-1 and LAG3 for use in a method of treating a subject having a squamous Stage IIIB/IIIC NSCLC or a Stage IV NSCLC, wherein the method comprises a dosing regimen comprising a bispecific antibody targeting PD-1 and LAG3, paclitaxel, and carboplatin, wherein the bispecific antibody comprises a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, and wherein the dosing regimen comprises administering to the subject one or more dosing cycles of (a) the bispecific antibody, wherein the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 15, a first light chain comprising the amino acid sequence of SEQ ID NO: 16, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 17, and a second light chain comprising the amino acid sequence of SEQ ID NO: 18; (b) paclitaxel, wherein the method comprises administering to the subject the paclitaxel at a dose of 200 mg/m² every three weeks; and (c) carboplatin, wherein the method comprises administering to the subject the carboplatin at a targeted AUC of 5 mg/mL • min every three weeks.

In some aspects, the squamous NSCLC is a locally advanced unresectable or metastatic squamous NSCLC, e.g., is (a) a Stage IIIB/IIIC squamous NSCLC; or (b) a Stage IV squamous NSCLC.

In some aspects, the squamous NSCLC (e.g., locally advanced unresectable or metastatic squamous NSCLC, e.g., Stage IIIB/IIIC or Stage IV squamous NSCLC) is first-line (1 L), e.g., the subject has not previously received a systemic anti-cancer therapy for locally advanced, unresectable or metastatic NSCLC. In some aspects, the subject has not received prior systemic treatment for metastatic NSCLC.

In some aspects, the squamous NSCLC is a PD-L1 -positive NSCLC. Exemplary methods for assessing PD-L1 expression level are provided, e.g., in Section III, below. In some aspects, a tumor sample from the NSCLC of the subject has a PD-L1 tumor proportion score (TPS) or a PD-L1 expression level on tumor cells (TCs) of <1%. In some aspects, a tumor sample from the NSCLC of the subject has a PD-L1 TPS or a PD-L1 expression level on TCs of between 1% and 49%. In some aspects, a tumor sample from the NSCLC of the subject has a PD-L1 TPS or a PD-L1 expression level on TCs of >50%. In other aspects, the squamous NSCLC is a PD-L1 -negative NSCLC.

In some aspects, the subject has a squamous NSCLC, and the control therapy comprises pembrolizumab, paclitaxel, and carboplatin and does not comprise the bispecific antibody. For example, in some aspects, the control therapy consists of pembrolizumab, paclitaxel, and carboplatin.

In some aspects, the bispecific antibody achieves at least 90% LAG3 receptor occupancy (RO) in the tumor, e.g., achieves at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% RO in the tumor.

In some aspects, the subject is a human.

C. TNBC

In another aspect, the disclosure provides a method for treating a subject having a triple-negative breast cancer (TNBC) (e.g., a locally advanced, unresectable or metastatic TNBC), the method comprising a dosing regimen comprising concurrently administering to the subject one or more dosing cycles of (a) a bispecific antibody targeting programmed cell death protein 1 (PD-1 ) and lymphocyte activation gene 3 (LAG3) comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, and (b) one or more dosing cycles of nab- paclitaxel.

In another aspect, the disclosure provides a bispecific antibody targeting PD-1 and LAG3 for use in a method of treating a subject having a TNBC (e.g., a locally advanced, unresectable or metastatic TNBC), wherein the method comprises a dosing regimen comprising a bispecific antibody targeting PD-1 and LAG3 and nab-paclitaxel, wherein the bispecific antibody comprises a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, and wherein the dosing regimen comprises concurrently administering to the subject (a) one or more dosing cycles of the bispecific antibody; and (b) one or more dosing cycles of nab-paclitaxel.

Exemplary bispecific antibodies targeting PD-1 and LAG3 are provided in Section IV, below. A particular example for a bispecific antibody targeting PD-1 and LAG3 is PD1 -LAG3 as defined herein. In some aspects, the method comprises administering the bispecific antibody (e.g., a bispecific antibody targeting PD-1 and LAG3 as provided in Section IV) at a fixed dose of 600 mg every three weeks (Q3W). In some aspects, the length of each of the one or more dosing cycles of the bispecific antibody is 21 days. In some aspects, the method comprises administering (e.g., intravenously administering) to the subject the bispecific antibody on Day 1 of each of the one or more dosing cycles. For example, the bispecific antibody may be administered by intravenous infusion over about 60 minutes or over about 30 minutes. In some aspects, the bispecific antibody is administered by intravenous infusion over a longer duration in a first cycle and over a shorter duration in a second or further dosing cycle: for example, in some aspects, the bispecific antibody is administered over 60 (± 15) minutes (e.g., over about 60 minutes) in a first dosing cycle and is administered over 30 (± 10) minutes (e.g., over about 30 minutes) in the one or more additional dosing cycles.

In some aspects, the method comprises administering to the subject the nab-paclitaxel at a dose of 100 mg/m² once a week for three weeks, followed by 1 week off. In some aspects, the length of each of the one or more dosing cycles of nab-paclitaxel is 28 days. In some aspects, the method comprises administering (e.g., intravenously administering) to the subject the nab-paclitaxel on Days 1 , 8, and 15 of each of the one or more dosing cycles. For example, in some aspects, the nab-paclitaxel is administered by intravenous infusion over about 30 minutes (e.g., over 30 minutes).

On days on which the bispecific antibody and the nab-paclitaxel are administered on the same day (e.g., on the first day of the dosing regimen), the bispecific antibody may be administered before the nab-paclitaxel. Alternatively, in some aspects, the nab-paclitaxel is administered before the bispecific antibody.

In some aspects, the dosing regimen comprises at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 15, 14, 15, 16, 17, 18, 19, 20, or more than 20 dosing cycles of the bispecific antibody (e.g., comprises at least 5 or at least 10 dosing cycles of the bispecific antibody). In some aspects, the dosing regimen comprises at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 15, 14, 15, 16, 17, 18, 19, 20, or more than 20 dosing cycles of the nab-paclitaxel. In some aspects, the dosing regimen comprises at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 15, 14, 15, 16, 17, 18, 19, 20, or more than 20 dosing cycles (e.g., at least 5 or at least 10 dosing cycles) of (a) the bispecific antibody and (b) nab-paclitaxel.

Accordingly, in some aspects, the method comprises administering to the subject the bispecific antibody at a fixed dose of 600 mg every three weeks and the nab-paclitaxel at a dose of 100 mg/m² once a week for three weeks, followed by 1 week off.

In some aspects, the TNBC (e.g., locally advanced, unresectable or metastatic TNBC) is first-line (1 L), e.g., the subject has not previously received a systemic anti-cancer therapy for locally advanced, unresectable or metastatic TNBC.

In some aspects, the TNBC is a PD-L1 -positive TNBC. Exemplary methods for assessing PD-L1 expression level are provided, e.g., in Section III, below. In some aspects, the PD-L1 -positive TNBC has a PD-L1 combined positive score (CPS) of > 10, as measured using the pharmDx 22C3 IHC assay; has a PD-L1 tumor area positivity score (TAP) of > 5%, as measured using the Ventana SP263 IHC assay; and/or has a PD-L1 -positive immune cell (IC) fraction of > 1%, as measured using the Ventana SP142 IHC assay. In other aspects, the TNBC is a PD-L1 -negative TNBC.

In a particular aspect, the disclosure provides a method for treating a subject having a locally advanced, unresectable or metastatic TNBC, wherein the method comprises a dosing regimen comprising concurrently administering to the subject (a) one or more dosing cycles of a bispecific antibody targeting PD-1 and LAG3 comprising a first antigen-binding domain that specifically binds to PD- 1 and a second antigen-binding domain that specifically binds to LAG3, wherein the method comprises administering to the subject the bispecific antibody at a fixed dose of 600 mg every three weeks, and wherein the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 15, a first light chain comprising the amino acid sequence of SEQ ID NO: 16, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 17, and a second light chain comprising the amino acid sequence of SEQ ID NO: 18; and (b) one or more dosing cycles of nab-paclitaxel, wherein the method comprises administering to the subject the nab-paclitaxel at a dose of 100 mg/m² once a week for three weeks, followed by 1 week off.

Clinical proof-of-concept for the dual inhibition of PD-1 and LAG3 was recently provided by the combination of relatlimab and nivolumab in patients with previously untreated metastatic or unresectable melanoma (Tawbi et al., N Engl J Med, 386(1 ): 24-34, 2022). By targeting both PD-1 and LAG-3 on dysfunctional tumor-specific T lymphocytes, bispecific antibodies targeting PD-1 and LAG3 aim to restore an effective anti-tumor immune-response and to provide even more survival benefit to cancer patients than the currently available checkpoint inhibitors. By preferentially targeting PD-1 /LAG-3 co-expressing dysfunctional T cells and potentially reduced targeting of LAG-3 expressing Tregs in the tumor microenvironment, bispecific antibodies targeting PD-1 and LAG3 might avoid reinvigorating Treg mediated immunosuppressive effects while restoring the anti-tumor immune response.

In some aspects, the method results in an increase in progression-free survival (PFS) (e.g., an increase of at least 1 %, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, or more than 100%, e.g., an increase of 1 -5%, 5-10%, 10-15%, 15- 20%, 20-25%, 25-30%, 30-35%, 35-40%, 40-45%, 45-50%, 50-55%, 55-60%, 60-65%, 65-70%, 70-75%, 75-80%, 80-85%, 85-90%, 90-95%, 95-100%, or more than 100%) as compared to a reference PFS. In some aspects, the reference PFS is a PFS of a population of subjects who have received a control therapy.

In some aspects, the method results in an increase in objective response rate (ORR) (e.g., an increase of at least 1 %, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, or more than 100%, e.g., an increase of 1 -5%, 5-10%, 10-15%, 15- 20%, 20-25%, 25-30%, 30-35%, 35-40%, 40-45%, 45-50%, 50-55%, 55-60%, 60-65%, 65-70%, 70-75%, 75-80%, 80-85%, 85-90%, 90-95%, 95-100%, or more than 100%) in a population of subjects treated according to the method as compared to a reference ORR. In some aspects, the reference ORR is an ORR of a population of subjects who have received a control therapy.

In some aspects, the method results in an increase in duration of response (DOR) (e.g., an increase of at least 1 %, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, or more than 100%, e.g., an increase of 1 -5%, 5-10%, 10-15%, 15- 20%, 20-25%, 25-30%, 30-35%, 35-40%, 40-45%, 45-50%, 50-55%, 55-60%, 60-65%, 65-70%, 70-75%, 75-80%, 80-85%, 85-90%, 90-95%, 95-100%, or more than 100%) as compared to a reference DOR. In some aspects, the reference DOR is a DOR of a population of subjects who have received a control therapy.

In some aspects, the method results in an increase in overall survival (OS) (e.g., an increase of at least 1 %, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, or more than 100%, e.g., an increase of 1 -5%, 5-10%, 10-15%, 15-20%, 20- 25%, 25-30%, 30-35%, 35-40%, 40-45%, 45-50%, 50-55%, 55-60%, 60-65%, 65-70%, 70-75%, 75-80%, 80-85%, 85-90%, 90-95%, 95-100%, or more than 100%) as compared to a reference OS. In some aspects, the reference OS is an OS of a population of subjects who have received a control therapy.

In some aspects, the method results in an increase in PFS rate (e.g., an increase of at least 1 %, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, or more than 100%, e.g., an increase of 1 -5%, 5-10%, 10-15%, 15-20%, 20-25%, 25-30%, 30-35%, 35-40%, 40-45%, 45-50%, 50-55%, 55-60%, 60-65%, 65-70%, 70-75%, 75-80%, 80-85%, 85- 90%, 90-95%, 95-100%, or more than 100%) at 12 months as compared to a reference PFS rate at 12 months. In some aspects, the reference PFS rate is a PFS rate of a population of subjects who have received a control therapy.

In some aspects, the method results in an increase in PFS rate at 12 months (e.g., an increase of at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, or more than 100%, e.g., an increase of 1 -5%, 5-10%, 10-15%, 15-20%, 20- 25%, 25-30%, 30-35%, 35-40%, 40-45%, 45-50%, 50-55%, 55-60%, 60-65%, 65-70%, 70-75%, 75-80%, 80-85%, 85-90%, 90-95%, 95-100%, or more than 100%) as compared to a reference PFS rate at 12 months. In some aspects, the reference PFS rate is a PFS rate of a population of subjects who have received a control therapy.

In some aspects, the control therapy comprises pembrolizumab and nab-paclitaxel and does not comprise the bispecific antibody. For example, in some aspects, the control therapy consists of pembrolizumab and nab-paclitaxel.

In some aspects, the subject is a human.

III. Assessment of PD-L1 Expression

The expression of PD-L1 may be assessed in a subject treated according to any of the methods and compositions for use described herein. The methods and compositions for use may include determining the expression level of PD-L1 in a biological sample (e.g., a tumor sample) obtained from the subject having a cancer (e.g., an NSCLC (e.g., a squamous or non-squamous NSCLC, e.g., a Stage IIIB/IIIC or Stage IV squamous or non-squamous NSCLC) or a TNBC (e.g., a locally advanced, unresectable or metastatic TNBC)). In other examples, the expression level of PD-L1 in a biological sample (e.g., a tumor sample) obtained from the subject has been determined prior to initiation of treatment or after initiation of treatment. PD-L1 expression may be determined using any suitable approach. For example, PD-L1 expression may be determined as described in U.S. Patent Publication Nos. US 20180030138 A1 and US 20180037655 A1 . Any suitable tumor sample may be used, e.g., a formalin-fixed and paraffin-embedded (FFPE) tumor sample, an archival tumor sample, a fresh tumor sample, or a frozen tumor sample.

In some aspects, a cancer (e.g., NSCLC) or a sample therefrom has a PD-L1 tumor proportion score (TPS) or a PD-L1 expression level on tumor cells (TCs) of <1%. In some aspects, a tumor sample from the NSCLC of the subject has a PD-L1 TPS or a PD-L1 expression level on TCs of between 1% and 49%. In some aspects, a tumor sample from the NSCLC of the subject has a PD-L1 TPS or a PD-L1 expression level on TCs of >50%.

In some aspects, a cancer (e.g., TNBC) or a sample therefrom is classified as PD-L1 -positive if it has a PD-L1 combined positive score (CPS) of > 10, as measured using the pharmDx 22C3 IHC assay; has a PD-L1 tumor area positivity score (TAP) of > 5%, as measured using the Ventana SP263 IHC assay; and/or has a PD-L1 -positive immune cell (IC) fraction of > 1%, as measured using the Ventana SP142 IHC assay. CPS is the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100. IC is defined as the presence of discernible PD-L1 staining of any intensity in tumor-infiltrating immune cells covering the tumor area occupied by tumor cells, associated intratumoral, and contiguous peritumoral stroma. TAP is defined as the percentage of stained tumor and immune cell within the total tumor area.

For example, PD-L1 expression may be determined in terms of the percentage of a tumor sample comprised by tumor-infiltrating immune cells expressing a detectable expression level of PD-L1 , as the percentage of tumor-infiltrating immune cells in a tumor sample expressing a detectable expression level of PD-L1 , and/or as the percentage of tumor cells in a tumor sample expressing a detectable expression level of PD-L1 . It is to be understood that in any of the preceding examples, the percentage of the tumor sample comprised by tumor-infiltrating immune cells may be in terms of the percentage of tumor area covered by tumor-infiltrating immune cells in a section of the tumor sample obtained from the subject, for example, as assessed by IHC using an anti-PD-L1 antibody (e.g., the SP142 antibody). Any suitable anti-PD-L1 antibody may be used, including, e.g., SP142 (Ventana), SP263 (Ventana), 22C3 (Dako), 28-8 (Dako), E1 L3N (Cell Signaling Technology), 4059 (ProSci, Inc.), h5H1 (Advanced Cell Diagnostics), and 9A11 . In some examples, the anti-PD-L1 antibody is SP142. In other examples, the anti-PD-L1 antibody is SP263.

In some examples, a tumor sample obtained from the subject has a detectable expression level of PD-L1 in less than 1% of the tumor cells in the tumor sample, in 1% or more of the tumor cells in the tumor sample, in from 1% to less than 5% of the tumor cells in the tumor sample, in 5% or more of the tumor cells in the tumor sample, in from 5% to less than 50% of the tumor cells in the tumor sample, or in 50% or more of the tumor cells in the tumor sample.

In some examples, a tumor sample obtained from the subject has a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise less than 1% of the tumor sample, more than 1% of the tumor sample, from 1% to less than 5% of the tumor sample, more than 5% of the tumor sample, from 5% to less than 10% of the tumor sample, or more than 10% of the tumor sample.

In some aspects, the cancer (e.g., NSCLC (e.g., squamous or non-squamous NSCLC, e.g., Stage IIIB/IIIC or Stage IV squamous or non-squamous NSCLC) or TNBC (e.g., a locally advanced, unresectable or metastatic TNBC)) of a subject treated according to any of the methods provided herein has a PD-L1 -positive tumor cell (TC) fraction or tumor-infiltrating immune cell (IC) fraction of < 5%. In some aspects, the esophageal cancer has a PD-L1 -positive TC fraction of <1%. In other aspects, the cancer of a subject treated according to any of the methods provided herein has a PD-L1 -positive TC fraction or IC fraction of > 5%. In some aspects, PD-L1 is detected using a Ventana SP142 IHC assay, a Ventana SP263 IHC assay, a pharmDx 22C3 IHC assay, or a pharmDx 28-8 IHC assay.

In some examples, tumor samples may be scored for PD-L1 positivity in tumor-infiltrating immune cells and/or in tumor cells according to the criteria for diagnostic assessment shown in Table 1 and/or Table 2, respectively. Table 1. Tumor-infiltrating immune cell (IC) IHC diagnostic criteria

Table 2. Tumor cell (TC) IHC diagnostic criteria

IV. Bispecific antibodies targeting PD-1 and LAG3

A. Exemplary bispecific antibodies that bind to PD-1 and LAG3

In one aspect, the invention provides a bispecific antibody comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, wherein said first antigen-binding domain specifically binding to PD-1 comprises a VH domain comprising:

(i) an HVR-H1 comprising the amino acid sequence of GFSFSSY (SEQ ID NO: 1 ),

(ii) an HVR-H2 comprising the amino acid sequence GGR, and

(iii) an HVR-H3 comprising an amino acid sequence of TGRVYFALD (SEQ ID NO: 2); and a VL domain comprising (i) an HVR-L1 comprising the amino acid sequence of SESVDTSDNSF (SEQ ID NO: 3);

(ii) an HVR-L2 comprising the amino acid sequence RSS, and

(iii) an HVR-L3 comprising the amino acid sequence of NYDVPW (SEQ ID NO: 4). In one aspect, the bispecific antibody comprises a Fc domain that is an IgG. In some aspects, the Fc domain is an IgG 1 Fc domain or an lgG4 Fc domain. In some aspects, the Fc domain has reduced or even abolished effector function. In particular, the Fc domain may comprisee one or more amino acid substitutions that reduces binding to an Fc receptor, in particular towards Fey receptor.

In a further aspect, provided herein is a bispecific antibody comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, wherein the bispecific antibody comprises a Fc domain that is an IgG, particularly an IgG 1 Fc domain or an lgG4 Fc domain and wherein the Fc domain comprises one or more amino acid substitutions that reduces binding to an Fc receptor, in particular towards Fey receptor.

In another aspect, provided herein is a bispecific antibody comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, wherein the second antigen-binding domain that specifically binds to LAG3 comprises a VH domain comprising:

(i) an HVR-H1 comprising the amino acid sequence of DYTMN (SEQ ID NO: 7),

(ii) an HVR-H2 comprising the amino acid sequence of VISWDGGGTYYTDSVKG (SEQ ID NO: 8), and

(iii) an HVR-H3 comprising an amino acid sequence of GLTDTTLYGSDY (SEQ ID NO: 9); and a VL domain comprising

(i) an HVR-L1 comprising the amino acid sequence of RASQSISSYLN (SEQ ID NO: 10),

(ii) an HVR-L2 comprising the amino acid sequence of AASTLQS (SEQ ID NO: 11 ), and

(iii) an HVR-L3 comprising the amino acid sequence of QQTYSSPLT (SEQ ID NO: 12).

(i) an HVR-H1 comprising the amino acid sequence of GFSFSSY (SEQ ID NO: 1 ),

(ii) an HVR-H2 comprising the amino acid sequence GGR, and

(iii) an HVR-H3 comprising an amino acid sequence of TGRVYFALD (SEQ ID NO: 2); and a VL domain comprising

(i) an HVR-L1 comprising the amino acid sequence of SESVDTSDNSF (SEQ ID NO: 3);

(ii) an HVR-L2 comprising the amino acid sequence RSS, and the second antigen-binding domain that specifically binds to LAG3 comprises a VH domain comprising:

(i) an HVR-H1 comprising the amino acid sequence of DYTMN (SEQ ID NO: 7),

(iii) an HVR-L3 comprising the amino acid sequence of QQTYSSPLT (SEQ ID NO: 12). In a further aspect, provided herein is a bispecific antibody comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, wherein the first antigen-binding domain specifically binding to PD-1 comprises a VH domain comprising the amino acid sequence of EVQLLESGGGLVQPGGSLRLSCAASGFSFSSYTMSWVRQAPGKGLEWVATISGGGRDIYYPDSV KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCVLLTGRVYFALDSWGQGTLVTVSS (SEQ ID NO: 5) and a VL domain comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINCKASESVDTSDNSFIHWYQQKPGQSPKLLIYRSSTLESGVPDRF SGSGSGTDFTLTISSLQAEDVAVYYCQQNYDVPWTFGQGTKVEIK (SEQ ID NO: 6).

In another aspect, provided herein is a bispecific antibody comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, wherein the second antigen-binding domain specifically binding to LAG3 comprises a VH domain comprising the amino acid sequence of EVQLLESGGGLVQPGGSLRL SCAASGFIFDDYTMNWVRQAPGKGLEWVAVISWDGGGTYYTDSVKGRFTISRDDFKNTLY LQMNSLRAEDTAVYYCAKGLTDTTLYGSDYWGQGTLVTVSS (SEQ ID NO: 13) and a VL domain comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSG SGTDFTLTISSLQPEDFATYYCQQ TYSSPLTFGGGTKVEIK (SEQ ID NO: 14).

In another aspect, the invention provides a bispecific antibody comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, wherein the first antigen-binding domain specifically binding to PD-1 comprises a VH domain comprising the amino acid sequence of EVQLLESGGGLVQPGGSLRLSCAASGFSFSSYTMSWVRQAPGKGLEWVATISGGGRDIYYPDSVKGRF TISRDNSKNTLYLQMNSLRAEDTAVYYCVLLTGRVYFALDSWGQGTLVTVSS (SEQ ID NO: 5) and a VL domain comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINCKASESVDTSDNSFIHWYQQKPGQSPKLLIYRSSTLESGVPDRFSGSG SGTDFTLTISSLQAEDVAVYYCQQNYDVPWTFGQGTKVEIK (SEQ ID NO: 6); and the second antigenbinding domain specifically binding to LAG3 comprises a VH domain comprising the amino acid sequence of EVQLLESGGGLVQPGGSLRLSCAASGFIFDDYTMNWVRQAPGKGLEWVAVISWDGGGTYYTDSVKGR FTISRDDFKNTLY LQMNSLRAEDTAVYYCAKGLTDTTLYGSDYWGQGTLVTVSS (SEQ ID NO: 13) and a VL domain comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASTLQSGVPSRFSGSGSGTD FTLTISSLQPEDFATYYCQQ TYSSPLTFGGGTKVEIK (SEQ ID NO: 14).

In one aspect, the bispecific antibody targeting PD-1 and LAG3 comprises a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, wherein the first antigen-binding domain specifically binding to PD-1 comprises a VH domain having at least 90% identity to (e.g., having 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more than 99% identity to) the amino acid sequence of SEQ ID NO: 5 and a VL domain having at least 90% identity to (e.g., having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more than 99% identity to) the amino acid sequence of SEQ ID NO: 6. In one aspect, the first antigen-binding domain specifically binding to PD-1 comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 5 and a VL domain comprising the amino acid sequence of SEQ ID NO: 6. In one aspect, the bispecific antibody targeting PD-1 and LAG3 comprises a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, wherein the second antigen-binding domain specifically binding to LAG3 comprises a VH domain having at least 90% identity to (e.g., having 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more than 99% identity to) the amino acid sequence of SEQ ID NO: 13 and a VL domain having at least 90% identity to (e.g., having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more than 99% identity to) the amino acid sequence of SEQ ID NO: 14. In one aspect, the second antigen-binding domain specifically binding to LAG3 comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 13 and a VL domain comprising the amino acid sequence of SEQ ID NO: 14.

In one aspect, the bispecific antibody targeting PD-1 and LAG3 comprises a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, wherein the first antigen-binding domain specifically binding to PD-1 comprises a VH domain having at least 90% identity to (e.g., having 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more than 99% identity to) the amino acid sequence of SEQ ID NO: 5 and a VL domain having at least 90% identity to (e.g., having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more than 99% identity to) the amino acid sequence of SEQ ID NO: 6 and the second antigen-binding domain specifically binding to LAG3 comprises a VH domain having at least 90% identity to (e.g., having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more than 99% identity to) the amino acid sequence of SEQ ID NO: 13 and a VL domain having at least 90% identity to (e.g., having 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more than 99% identity to) the amino acid sequence of SEQ ID NO: 14.

In another aspect, provided is a bispecific antibody comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, wherein the first antigen-binding domain specifically binding to PD-1 comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 5 and a VL domain comprising the amino acid sequence of SEQ ID NO: 6, and the second antigen-binding domain specifically binding to LAG3 comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 13 and a VL domain comprising the amino acid sequence of SEQ ID NO: 14.

In a further aspect, the bispecific antibody comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3 is a human, humanized or chimeric antibody. In particular, it is a humanized or chimeric antibody.

In one aspect, the bispecific antibody comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3 is bivalent. This means that the bispecific antibody comprises one antigen-binding domain that specifically binds to PD-1 and one antigen-binding domain that specifically binds to LAG3 (1 +1 format).

In one aspect, provided is a bispecific antibody comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, wherein the bispecific antibody comprises an Fc domain, a first Fab fragment comprising the antigen-binding domain that specifically binds to PD-1 and a second Fab fragment comprising the antigen-binding domain that specifically binds to LAG3. In a particular aspect, in one of the Fab fragments the variable domains VL and VH are replaced by each other so that the VH domain is part of the light chain and the VL domain is part of the heavy chain. In a particular aspect, in the first Fab fragment comprising the antigen-binding domain that specifically binds to PD-1 the variable domains VL and VH are replaced by each other.

In a particular aspect, provided is a bispecific antibody comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, wherein the bispecific antibody comprises a first heavy chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 15, a first light chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 16, a second heavy chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 17, and a second light chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO:18. For example, in one aspect, the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 15, a first light chain comprising the amino acid sequence of SEQ ID NO: 16, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 17, and a second light chain comprising the amino acid sequence of SEQ ID NO:18 (PD1 - LAG3).

In a further aspect, provided is a bispecific antibody comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, wherein the bispecific antibody comprises an Fc domain, a first Fab fragment comprising the antigenbinding domain that specifically binds to PD-1 and a second Fab fragment comprising the antigen-binding domain that specifically binds to LAG3 that is fused to the C-terminus of the Fc domain. Particularly, the Fab fragment comprising the antigen-binding domain that specifically binds to LAG3 is fused to the C- terminus of the Fc domain via its VH domain (trans 1 +1 format).

In one aspect, the bispecific antibody comprises a first heavy chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 15, a first light chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO:

16, a second heavy chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 37, and a second light chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 18. More particularly, the bispecific antibody may comprise a first heavy chain comprising an amino acid sequence of SEQ ID NO: 15, a first light chain comprising an amino acid sequence of SEQ ID NO: 16, a second heavy chain comprising an amino acid sequence of SEQ ID NO: 37, and a second light chain comprising an amino acid sequence of SEQ ID NO: 18.

In particular aspects, the bispecific antibody targeting PD-1 and LAG3 is RO7247669 or tobemstomig. “Tobemstomig” is a humanized lgG1 -based bispecfifc antibody that comprises monovalent binding to PD-1 and monovalent binding to LAG3. The bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 15, a first light chain comprising the amino acid sequence of SEQ ID NO: 16, a second heavy chain comprising the amino acid sequence of SEQ ID NO:

17, and a second light chain comprising the amino acid sequence of SEQ ID NO: 18. Tobemstomig is also described in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Recommended INN: List 89, Vol. 37, No. 1 , published 2023 (page 203), see also correction in Recommended INN: List 90, Vol 37, No.3, published 2023 (page 907) and has the CAS Registry No: 2648839-43-2. Fc domain modifications reducing Fc receptor binding and/or effector function

In certain aspects, provided is a bispecific antibody comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, wherein the bispecific antibody comprises a Fc domain comprising one or more amino acid modifications that reduce binding to an Fc receptor, in particular towards Fey receptor, and reduce or abolish effector function.

In certain aspects, one or more amino acid modifications may be introduced into the Fc region of an antibody provided herein, thereby generating an Fc region variant. The Fc region variant may comprise a human Fc region sequence (e.g., a human lgG1 , lgG2, lgG3 or lgG4 Fc region) comprising an amino acid modification (e.g., a substitution) at one or more amino acid positions.

The following section describes preferred aspects of the bispecific antigen binding molecules of the invention comprising Fc domain modifications reducing Fc receptor binding and/or effector function. In one aspect, the invention relates to a bispecific antibody comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, wherein the Fc domain comprises one or more amino acid substitution that reduces binding to an Fc receptor, in particular towards Fey receptor. In particular, the Fc domain is of human IgG 1 subclass with the amino acid mutations L234A, L235A and P329G (numbering according to Kabat EU index).

The Fc domain confers favorable pharmacokinetic properties to the bispecific antibodies of the invention, including a long serum half-life which contributes to good accumulation in the target tissue and a favorable tissue-blood distribution ratio. At the same time it may, however, lead to undesirable targeting of the bispecific antibodies of the invention to cells expressing Fc receptors rather than to the preferred antigen-bearing cells. Accordingly, in particular embodiments the Fc domain of the the bispecific antibodies of the invention exhibits reduced binding affinity to an Fc receptor and/or reduced effector function, as compared to a native IgG Fc domain, in particular an IgG 1 Fc domain or an lgG4 Fc domain. More particularly, the Fc domain is an IgG 1 FC domain.

In one such aspect the Fc domain (or the bispecific antigen binding molecule of the invention comprising said Fc domain) exhibits less than 50%, preferably less than 20%, more preferably less than 10% and most preferably less than 5% of the binding affinity to an Fc receptor, as compared to a native IgG 1 Fc domain (or the bispecific antigen binding molecule of the invention comprising a native IgG 1 Fc domain), and/or less than 50%, preferably less than 20%, more preferably less than 10% and most preferably less than 5% of the effector function, as compared to a native IgG 1 Fc domain (or the bispecific antigen binding molecule of the invention comprising a native IgG 1 Fc domain). In one aspect, the Fc domain (or the bispecific antigen binding molecule of the invention comprising said Fc domain) does not substantially bind to an Fc receptor and/or induce effector function. In a particular aspect the Fc receptor is an Fey receptor. In one aspect, the Fc receptor is a human Fc receptor. In one aspect, the Fc receptor is an activating Fc receptor. In a specific aspect, the Fc receptor is an activating human Fey receptor, more specifically human FcyRllla, FcyRI or FcyRlla, most specifically human FcyRllla. In one aspect, the Fc receptor is an inhibitory Fc receptor. In a specific aspect, the Fc receptor is an inhibitory human Fey receptor, more specifically human FcyRIIB. In one aspect the effector function is one or more of CDC, ADCC, ADCP, and cytokine secretion. In a particular aspect, the effector function is ADCC. In one aspect, the Fc domain domain exhibits substantially similar binding affinity to neonatal Fc receptor (FcRn), as compared to a native IgG 1 Fc domain. Substantially similar binding to FcRn is achieved when the Fc domain (or the the bispecific antigen binding molecule of the invention comprising said Fc domain) exhibits greater than about 70%, particularly greater than about 80%, more particularly greater than about 90% of the binding affinity of a native IgG 1 Fc domain (or the the bispecific antigen binding molecule of the invention comprising a native IgG 1 Fc domain) to FcRn.

In a particular aspect, the Fc domain is engineered to have reduced binding affinity to an Fc receptor and/or reduced effector function, as compared to a non-engineered Fc domain. In a particular aspect, the Fc domain of the bispecific antigen binding molecule of the invention comprises one or more amino acid mutation that reduces the binding affinity of the Fc domain to an Fc receptor and/or effector function. Typically, the same one or more amino acid mutation is present in each of the two subunits of the Fc domain. In one aspect, the amino acid mutation reduces the binding affinity of the Fc domain to an Fc receptor. In another aspect, the amino acid mutation reduces the binding affinity of the Fc domain to an Fc receptor by at least 2-fold, at least 5-fold, or at least 10-fold. In one aspect, the bispecific antigen binding molecule of the invention comprising an engineered Fc domain exhibits less than 20%, particularly less than 10%, more particularly less than 5% of the binding affinity to an Fc receptor as compared to bispecific antibodies of the invention comprising a non-engineered Fc domain. In a particular aspect, the Fc receptor is an Fey receptor. In other aspects, the Fc receptor is a human Fc receptor. In one aspect, the Fc receptor Is an inhibitory Fc receptor. In a specific aspect, the Fc receptor is an inhibitory human Fey receptor, more specifically human FcyRIIB. In some aspects the Fc receptor is an activating Fc receptor. In a specific aspect, the Fc receptor is an activating human Fey receptor, more specifically human FcyRllla, FcyRI or FcyRlla, most specifically human FcyRllla. Preferably, binding to each of these receptors is reduced. In some aspects, binding affinity to a complement component, specifically binding affinity to C1q, is also reduced. In one aspect, binding affinity to neonatal Fc receptor (FcRn) is not reduced. Substantially similar binding to FcRn, i.e. preservation of the binding affinity of the Fc domain to said receptor, is achieved when the Fc domain (or the bispecific antigen binding molecule of the invention comprising said Fc domain) exhibits greater than about 70% of the binding affinity of a non-engineered form of the Fc domain (or the bispecific antigen binding molecule of the invention comprising said non-engineered form of the Fc domain) to FcRn. The Fc domain, or the the bispecific antigen binding molecule of the invention comprising said Fc domain, may exhibit greater than about 80% and even greater than about 90% of such affinity. In certain embodiments the Fc domain of the bispecific antigen binding molecule of the invention is engineered to have reduced effector function, as compared to a non-engineered Fc domain. The reduced effector function can include, but is not limited to, one or more of the following: reduced complement dependent cytotoxicity (CDC), reduced antibody-dependent cell-mediated cytotoxicity (ADCC), reduced antibody-dependent cellular phagocytosis (ADCP), reduced cytokine secretion, reduced immune complex-mediated antigen uptake by antigen-presenting cells, reduced binding to NK cells, reduced binding to macrophages, reduced binding to monocytes, reduced binding to polymorphonuclear cells, reduced direct signaling inducing apoptosis, reduced dendritic cell maturation, or reduced T cell priming.

Antibodies with reduced effector function include those with substitution of one or more of Fc region residues 238, 265, 269, 270, 297, 327 and 329 (U.S. Patent No. 6,737,056). Such Fc mutants include Fc mutants with substitutions at two or more of amino acid positions 265, 269, 270, 297 and 327, including the so-called “DANA” Fc mutant with substitution of residues 265 and 297 to alanine (US Patent No. 7,332,581 ). Certain antibody variants with improved or diminished binding to FcRs are described, (e.g. U.S. Patent No. 6,737,056; WO 2004/056312, and Shields, R.L. et al., J. Biol. Chem. 276 (2001 ) 6591 -6604).

In one aspect of the invention, the Fc domain comprises an amino acid substitution at a position of E233, L234, L235, N297, P331 and P329. In some aspects, the Fc domain comprises the amino acid substitutions L234A and L235A (“LALA”). In one such embodiment, the Fc domain is an IgG 1 Fc domain, particularly a human IgG 1 Fc domain. In one aspect, the Fc domain comprises an amino acid substitution at position P329. In a more specific aspect, the amino acid substitution is P329A or P329G, particularly P329G. In one embodiment the Fc domain comprises an amino acid substitution at position P329 and a further amino acid substitution selected from the group consisting of E233P, L234A, L235A, L235E, N297A, N297D or P331 S. In more particular embodiments the Fc domain comprises the amino acid mutations L234A, L235A and P329G (“P329G LALA”). The “P329G LALA” combination of amino acid substitutions almost completely abolishes Fey receptor binding of a human IgG 1 Fc domain, as described in PCT Patent Application No. WO 2012/130831 A1 . Said document also describes methods of preparing such mutant Fc domains and methods for determining its properties such as Fc receptor binding or effector functions. Such antibody is an IgG 1 with mutations L234A and L235A or with mutations L234A, L235A and P329G (numbering according to EU index of Kabat et al., Sequences of Proteins of Immunological Interest, 5^th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991 ).

In one aspect, the bispecific antibody of the invention comprises (all positions according to EU index of Kabat) (i) a homodimeric Fc-region of the human lgG1 subclass optionally with the mutations P329G, L234A and L235A, or (ii) a homodimeric Fc-region of the human lgG4 subclass optionally with the mutations P329G, S228P and L235E, or (iii) a homodimeric Fc-region of the human IgG 1 subclass optionally with the mutations P329G, L234A, L235A, I253A, H310A, and H435A, or optionally with the mutations P329G, L234A, L235A, H310A, H433A, and Y436A, or (iv) a heterodimeric Fc-region wherein one Fc-region polypeptide comprises the mutation T366W, and the other Fc-region polypeptide comprises the mutations T366S, L368A and Y407V, or wherein one Fc-region polypeptide comprises the mutations T366W and Y349C, and the other Fc-region polypeptide comprises the mutations T366S, L368A, Y407V, and S354C, or wherein one Fc-region polypeptide comprises the mutations T366W and S354C, and the other Fc-region polypeptide comprises the mutations T366S, L368A, Y407V and Y349C, or (v) a heterodimeric Fc-region of the human IgG 1 subclass wherein both Fc-region polypeptides comprise the mutations P329G, L234A and L235A and one Fc-region polypeptide comprises the mutation T366W, and the other Fc-region polypeptide comprises the mutations T366S, L368A and Y407V, or wherein one Fc-region polypeptide comprises the mutations T366W and Y349C, and the other Fc-region polypeptide comprises the mutations T366S, L368A, Y407V, and S354C, or wherein one Fc- region polypeptide comprises the mutations T366W and S354C, and the other Fc-region polypeptide comprises the mutations T366S, L368A, Y407V and Y349C.

In one aspect, the Fc domain is an lgG4 Fc domain. In a more specific embodiment, the Fc domain is an lgG4 Fc domain comprising an amino acid substitution at position S228 (Kabat numbering), particularly the amino acid substitution S228P. In a more specific embodiment, the Fc domain is an lgG4 Fc domain comprising amino acid substitutions L235E and S228P and P329G. This amino acid substitution reduces in vivo Fab arm exchange of lgG4 antibodies (see Stubenrauch et al., Drug Metabolism and Disposition 38, 84-91 (2010)). Thus, in one aspect, provided is a bispecific antibody, comprising (all positions according to EU index of Kabat) a heterodimeric Fc-region of the human lgG4 subclass wherein both Fc-region polypeptides comprise the mutations P329G, S228P and L235E and one Fc-region polypeptide comprises the mutation T366W, and the other Fc-region polypeptide comprises the mutations T366S, L368A and Y407V, or wherein one Fc-region polypeptide comprises the mutations T366W and Y349C, and the other Fc-region polypeptide comprises the mutations T366S, L368A, Y407V, and S354C, or wherein one Fc-region polypeptide comprises the mutations T366W and S354C, and the other Fc-region polypeptide comprises the mutations T366S, L368A, Y407V and Y349C.

Antibodies with increased half lives and improved binding to the neonatal Fc receptor (FcRn), which is responsible for the transfer of maternal IgGs to the fetus (Guyer, R.L. et al., J. Immunol. 117 (1976) 587-593, and Kim, J.K. et al., J. Immunol. 24 (1994) 2429-2434), are described in US 2005/0014934. Those antibodies comprise an Fc region with one or more substitutions therein which improve binding of the Fc region to FcRn. Such Fc variants include those with substitutions at one or more of Fc region residues: 238, 256, 265, 272, 286, 303, 305, 307, 311 , 312, 317, 340, 356, 360, 362, 376, 378, 380, 382, 413, 424 or 434, e.g., substitution of Fc region residue 434 (US Patent No. 7,371 ,826). See also Duncan, A.R. and Winter, G., Nature 322 (1988) 738-740; US 5,648,260; US 5,624,821 ; and WO 94/29351 concerning other examples of Fc region variants.

Binding to Fc receptors can be easily determined, e.g., by ELISA, or by Surface Plasmon Resonance (SPR) using standard instrumentation such as a BIAcore instrument (GE Healthcare), and Fc receptors such as may be obtained by recombinant expression. A suitable such binding assay is described herein. Alternatively, binding affinity of Fc domains or cell activating bispecific antigen binding molecules comprising an Fc domain for Fc receptors may be evaluated using cell lines known to express particular Fc receptors, such as human NK cells expressing Fcyllla receptor. Effector function of an Fc domain, or bispecific antibodies of the invention comprising an Fc domain, can be measured by methods known in the art. A suitable assay for measuring ADCC is described herein. Other examples of in vitro assays to assess ADCC activity of a molecule of interest are described in U.S. Patent No. 5,500,362; Hellstrom et al. Proc Natl Acad Sci USA 83, 7059-7063 (1986) and Hellstrom et al., Proc Natl Acad Sci USA 82, 1499-1502 (1985); U.S. Patent No. 5,821 ,337; Bruggemann et al., J Exp Med 166, 1351 -1361 (1987). Alternatively, non-radioactive assays methods may be employed (see, for example, ACTI™ nonradioactive cytotoxicity assay for flow cytometry (CellTechnology, Inc. Mountain View, CA); and CytoTox 96® non-radioactive cytotoxicity assay (Promega, Madison, Wl)). Useful effector cells for such assays include peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells. Alternatively, or additionally, ADCC activity of the molecule of interest may be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al., Proc Natl Acad Sci USA 95, 652-656 (1998).

The following section describes preferred aspects of the bispecific antibodies of the invention comprising Fc domain modifications reducing Fc receptor binding and/or effector function. In one aspect, the invention relates to the bispecific comprising a first antigen-binding domain that specifically binds PD- 1 and a second antigen-binding domain that specifically binds to LAG3, wherein the Fc domain comprises one or more amino acid substitution that reduces the binding affinity of the antibody to an Fc receptor, in particular towards Fey receptor. In another aspect, the invention relates to the bispecific antibody comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigenbinding domain that specifically binds to LAG3, wherein the Fc domain comprises one or more amino acid substitution that reduces effector function. In particular aspect, the Fc domain is of human IgG 1 subclass with the amino acid mutations L234A, L235A and P329G (numbering according to Kabat EU index).

Fc domain modifications promoting heterodimerization

The bispecific antigen binding molecules of the invention comprise different antigen-binding domains, fused to one or the other of the two subunits of the Fc domain, thus the two subunits of the Fc domain may be comprised in two non-identical polypeptide chains. Recombinant co-expression of these polypeptides and subsequent dimerization leads to several possible combinations of the two polypeptides. To improve the yield and purity of the bispecific antibodies of the invention in recombinant production, it will thus be advantageous to introduce in the Fc domain of the bispecific antigen binding molecules of the invention a modification promoting the association of the desired polypeptides.

Accordingly, in particular aspects the invention relates to a bispecific antibody comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, wherein the Fc domain comprises a modification promoting the association of the first and second subunit of the Fc domain. The site of most extensive protein-protein interaction between the two subunits of a human IgG Fc domain is in the CH3 domain of the Fc domain. Thus, in one aspect said modification is in the CH3 domain of the Fc domain.

In a specific aspect said modification is a so-called “knob-into-hole” modification, comprising a “knob” modification in one of the two subunits of the Fc domain and a “hole” modification in the other one of the two subunits of the Fc domain. Thus, the invention relates to a bispecific antibody comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding site that specifically binds to LAG3, wherein the first subunit of the Fc domain comprises knobs and the second subunit of the Fc domain comprises holes according to the knobs into holes method. In a particular aspect, the first subunit of the Fc domain comprises the amino acid substitutions S354C and T366W (EU numbering) and the second subunit of the Fc domain comprises the amino acid substitutions Y349C, T366S and Y407V (numbering according to Kabat EU index).

The knob-into-hole technology is described e.g., in US 5,731 ,168; US 7,695,936; Ridgway et al., Prot Eng 9, 617-621 (1996) and Carter, J Immunol Meth 248, 7-15 (2001 ). Generally, the method involves introducing a protuberance (“knob”) at the interface of a first polypeptide and a corresponding cavity (“hole”) in the interface of a second polypeptide, such that the protuberance can be positioned in the cavity so as to promote heterodimer formation and hinder homodimer formation. Protuberances are constructed by replacing small amino acid side chains from the interface of the first polypeptide with larger side chains (e.g., tyrosine or tryptophan). Compensatory cavities of identical or similar size to the protuberances are created in the interface of the second polypeptide by replacing large amino acid side chains with smaller ones (e.g., alanine or threonine).

Accordingly, in one aspect, in the CH3 domain of the first subunit of the Fc domain of the bispecific antigen binding molecules of the invention an amino acid residue is replaced with an amino acid residue having a larger side chain volume, thereby generating a protuberance within the CH3 domain of the first subunit which is positionable in a cavity within the CH3 domain of the second subunit, and in the CH3 domain of the second subunit of the Fc domain an amino acid residue is replaced with an amino acid residue having a smaller side chain volume, thereby generating a cavity within the CH3 domain of the second subunit within which the protuberance within the CH3 domain of the first subunit is positionable. The protuberance and cavity can be made by altering the nucleic acid encoding the polypeptides, e.g., by site-specific mutagenesis, or by peptide synthesis. In a specific aspect, in the CH3 domain of the first subunit of the Fc domain the threonine residue at position 366 is replaced with a tryptophan residue (T366W), and in the CH3 domain of the second subunit of the Fc domain the tyrosine residue at position 407 is replaced with a valine residue (Y407V). In one aspect, in the second subunit of the Fc domain additionally the threonine residue at position 366 is replaced with a serine residue (T366S) and the leucine residue at position 368 is replaced with an alanine residue (L368A).

In yet a further aspect, in the first subunit of the Fc domain additionally the serine residue at position 354 is replaced with a cysteine residue (S354C), and in the second subunit of the Fc domain additionally the tyrosine residue at position 349 is replaced by a cysteine residue (Y349C). Introduction of these two cysteine residues leads to the formation of a disulfide bridge between the two subunits of the Fc domain, further stabilizing the dimer (Carter (2001 ), J Immunol Methods 248, 7-15). In a particular aspect, the first subunit of the Fc domain comprises the amino acid substitutions S354C and T366W (EU numbering) and the second subunit of the Fc domain comprises the amino acid substitutions Y349C, T366S and Y407V (numbering according to Kabat EU index).

But also other knobs-in-holes technologies as described by EP 1 870459, can be used alternatively or additionally. In one embodiment the multispecific antibody comprises the mutations R409D and K370E in the CH3 domain of the “knobs chain” and the mutations D399K and E357K in the CH3 domain of the “hole-chain” (numbering according to Kabat EU index).

In one aspect, the bispecific antibody comprises a T366W mutation in the CH3 domain of the “knobs chain” and the mutations T366S, L368A and Y407V in the CH3 domain of the “hole chain” and additionally the mutations R409D and K370E in the CH3 domain of the “knobs chain” and the mutations D399K and E357K in the CH3 domain of the “hole chain” (numbering according to the Kabat EU index).

In one aspect, the bispecific antibody comprises the mutations Y349C and T366W in one of the two CH3 domains and the mutations S354C, T366S, L368A and Y407V in the other of the two CH3 domains, or the multispecific antibody comprises the mutations Y349C and T366W in one of the two CH3 domains and the mutations S354C, T366S, L368A and Y407V in the other of the two CH3 domains and additionally the mutations R409D and K370E in the CH3 domain of the “knobs chain” and the mutations D399K and E357K in the CH3 domain of the “hole chain” (numbering according to the Kabat EU index).

In an alternative aspect, a modification promoting association of the first and the second subunit of the Fc domain comprises a modification mediating electrostatic steering effects, e.g., as described in PCT publication WO 2009/089004. Generally, this method involves replacement of one or more amino acid residues at the interface of the two Fc domain subunits by charged amino acid residues so that homodimer formation becomes electrostatically unfavorable but heterodimerization electrostatically favorable. Apart from the “knob-into-hole technology” other techniques for modifying the CH3 domains of the heavy chains of a multispecific antibody to enforce heterodimerization are known in the art. These technologies, especially the ones described in WO 96/27011 , WO 98/050431 , EP 1870459, WO 2007/110205, WO 2007/147901 , WO 2009/089004, WO 2010/129304, WO 2011 /90754, WO 2011/143545, WO 2012/058768, WO 2013/157954 and WO 2013/096291 are contemplated herein as alternatives to the “knob-into-hole technology” in combination with a bispecific antibody.

In one aspect, in the bispecific antibody the approach described in EP 1870459 is used to support heterodimerization of the first heavy chain and the second heavy chain of the multispecific antibody. This approach is based on the introduction of charged amino acids with opposite charges at specific amino acid positions in the CH3/CH3-domain-interface between both, the first and the second heavy chain.

Accordingly, in this aspect in the tertiary structure of the multispecific antibody the CH3 domain of the first heavy chain and the CH3 domain of the second heavy chain form an interface that is located between the respective antibody CH3 domains, wherein the respective amino acid sequences of the CH3 domain of the first heavy chain and the amino acid sequence of the CH3 domain of the second heavy chain each comprise a set of amino acids that is located within said interface in the tertiary structure of the antibody, wherein from the set of amino acids that is located in the interface in the CH3 domain of one heavy chain a first amino acid is substituted by a positively charged amino acid and from the set of amino acids that is located in the interface in the CH3 domain of the other heavy chain a second amino acid is substituted by a negatively charged amino acid. The bispecific antibody according to this aspect is herein also referred to as “CH3(+/-)-engineered bispecific antibody” (wherein the abbreviation “+/-” stands for the oppositely charged amino acids that were introduced in the respective CH3 domains).

In one aspect, in the CH3(+/-)-engineered bispecific antibody the positively charged amino acid is selected from K, R and H, and the negatively charged amino acid is selected from E or D.

In one aspect, in the CH3(+/-)-engineered bispecific antibody the positively charged amino acid is selected from K and R, and the negatively charged amino acid is selected from E or D.

In one aspect, in the CH3(+/-)-engineered bispecific antibody the positively charged amino acid is K, and the negatively charged amino acid is E.

In one aspect, in the CH3(+/-)-engineered bispecific antibody in the CH3 domain of one heavy chain the amino acid R at position 409 is substituted by D and the amino acid K at position is substituted by E, and in the CH3 domain of the other heavy chain the amino acid D at position 399 is substituted by K and the amino acid E at position 357 is substituted by K (numbering according to Kabat EU index).

In one aspect, the approach described in WO 2013/157953 is used to support heterodimerization of the first heavy chain and the second heavy chain of the multispecific antibody. In one embodiment in the CH3 domain of one heavy chain the amino acid T at position 366 is substituted by K, and in the CH3 domain of the other heavy chain the amino acid L at position 351 is substituted by D (numbering according to Kabat EU index). In another embodiment in the CH3 domain of one heavy chain the amino acid T at position 366 is substituted by K and the amino acid L at position 351 is substituted by K, and in the CH3 domain of the other heavy chain the amino acid L at position 351 is substituted by D (numbering according to Kabat EU index). In another aspect, in the CH3 domain of one heavy chain the amino acid T at position 366 is substituted by K and the amino acid L at position 351 is substituted by K, and in the CH3 domain of the other heavy chain the amino acid L at position 351 is substituted by D (numbering according to Kabat EU index). Additionally at least one of the following substitutions is comprised in the CH3 domain of the other heavy chain: the amino acid Y at position 349 is substituted by E, the amino acid Y at position 349 is substituted by D and the amino acid L at position 368 is substituted by E (numbering according to Kabat EU index). In one embodiment the amino acid L at position 368 is substituted by E (numbering according to Kabat EU index).

In one aspect, the approach described in WO 2012/058768 is used to support heterodimerization of the first heavy chain and the second heavy chain of the multispecific antibody. In one aspect, in the CH3 domain of one heavy chain the amino acid L at position 351 is substituted by Y and the amino acid Y at position 407 is substituted by A, and in the CH3 domain of the other heavy chain the amino acid T at position 366 is substituted by A and the amino acid K at position 409 is substituted by F (numbering according to Kabat EU index). In another embodiment, in addition to the aforementioned substitutions, in the CH3 domain of the other heavy chain at least one of the amino acids at positions 411 (originally T), 399 (originally D), 400 (originally S), 405 (originally F), 390 (originally N) and 392 (originally K) is substituted (numbering according to Kabat EU index). Preferred substitutions are:

- substituting the amino acid T at position 411 by an amino acid selected from N, R, Q, K, D, E and W (numbering according to Kabat EU index),

- substituting the amino acid D at position 399 by an amino acid selected from R, W, Y, and K (numbering according to Kabat EU index),

- substituting the amino acid S at position 400 by an amino acid selected from E, D, R and K (numbering according to Kabat EU index),

- substituting the amino acid F at position 405 by an amino acid selected from I, M, T, S, V and W (numbering according to Kabat EU index;

- substituting the amino acid N at position 390 by an amino acid selected from R, K and D (numbering according to Kabat EU index; and

- substituting the amino acid K at position 392 by an amino acid selected from V, M, R, L, F and E (numbering according to Kabat EU index).

In another aspect, the bispecific antibody is engineered according to WO 2012/058768), i.e. in the CH3 domain of one heavy chain the amino acid L at position 351 is substituted by Y and the amino acid Y at position 407 is substituted by A, and in the CH3 domain of the other heavy chain the amino acid T at position 366 is substituted by V and the amino acid K at position 409 is substituted by F (numbering according to Kabat EU index). In another embodiment of the multispecific antibody, in the CH3 domain of one heavy chain the amino acid Y at position 407 is substituted by A, and in the CH3 domain of the other heavy chain the amino acid T at position 366 is substituted by A and the amino acid K at position 409 is substituted by F (numbering according to Kabat EU index). In the last aforementioned embodiment, in the CH3 domain of the other heavy chain the amino acid K at position 392 is substituted by E, the amino acid T at position 411 is substituted by E, the amino acid D at position 399 is substituted by R and the amino acid S at position 400 is substituted by R (numbering according to Kabat EU index). In one aspect, the approach described in WO 2011/143545 is used to support heterodimerization of the first heavy chain and the second heavy chain of the multispecific antibody. In one aspect, amino acid modifications in the CH3 domains of both heavy chains are introduced at positions 368 and/or 409 (numbering according to Kabat EU index).

In one aspect, the approach described in WO 2011/090762 is used to support heterodimerization of the first heavy chain and the second heavy chain of the bispecific antibody. WO 2011/090762 relates to amino acid modifications according to the “knob-into-hole” (KiH) technology. In one embodiment in the CH3 domain of one heavy chain the amino acid T at position 366 is substituted by W, and in the CH3 domain of the other heavy chain the amino acid Y at position 407 is substituted by A (numbering according to Kabat EU index). In another embodiment in the CH3 domain of one heavy chain the amino acid T at position 366 is substituted by Y, and in the CH3 domain of the other heavy chain the amino acid Y at position 407 is substituted by T (numbering according to Kabat EU index).

In one aspect, the approach described in WO 2009/089004 is used to support heterodimerization of the first heavy chain and the second heavy chain of the bispecific antibody. In one embodiment in the CH3 domain of one heavy chain the amino acid K or N at position 392 is substituted by a negatively charged amino acid (in one embodiment by E or D, in one preferred embodiment by D), and in the CH3 domain of the other heavy chain the amino acid D at position 399 the amino acid E or D at position 356 or the amino acid E at position 357 is substituted by a positively charged amino acid (in one embodiment K or R, in one preferred embodiment by K, in one preferred embodiment the amino acids at positions 399 or 356 are substituted by K) (numbering according to Kabat EU index). In one further embodiment, in addition to the aforementioned substitutions, in the CH3 domain of the one heavy chain the amino acid K or R at position 409 is substituted by a negatively charged amino acid (in one embodiment by E or D, in one preferred embodiment by D) (numbering according to Kabat EU index). In one even further aspect, in addition to or alternatively to the aforementioned substitutions, in the CH3 domain of the one heavy chain the amino acid K at position 439 and/or the amino acid K at position 370 is substituted independently from each other by a negatively charged amino acid (in one embodiment by E or D, in one preferred embodiment by D) (numbering according to Kabat EU index).

In one aspect, the approach described in WO 2007/147901 is used to support heterodimerization of the first heavy chain and the second heavy chain of the multispecific antibody. In one embodiment in the CH3 domain of one heavy chain the amino acid K at position 253 is substituted by E, the amino acid D at position 282 is substituted by K and the amino acid K at position 322 is substituted by D, and in the

CH3 domain of the other heavy chain the amino acid D at position 239 is substituted by K, the amino acid

E at position 240 is substituted by K and the amino acid K at position 292 is substituted by D (numbering according to Kabat EU index).

The C-terminus of the heavy chain of the bispecific antibody as reported herein can be a complete C-terminus ending with the amino acid residues PGK. The C-terminus of the heavy chain can be a shortened C-terminus in which one or two of the C terminal amino acid residues have been removed. In one preferred aspect, the C-terminus of the heavy chain is a shortened C-terminus ending PG. In one aspect, the C-terminus of the heavy chain is a shortened C-terminus ending P.

In one aspect of all aspects as reported herein, a bispecific antibody comprising a heavy chain including a C-terminal CH3 domain as specified herein, comprises the C-terminal glycine-lysine dipeptide (G446 and K447, numbering according to Kabat EU index). In one embodiment of all aspects as reported herein, a bispecific antibody comprising a heavy chain including a C-terminal CH3 domain, as specified herein, comprises a C-terminal glycine residue (G446, numbering according to Kabat EU index).

/'. Modifications in the Fab domains

In one aspect, the invention relates to a bispecific antibody comprising a first Fab fragment that specifically binds to PD-1 and a second Fab fragment that specifically binds to LAG3, wherein in one of the Fab fragments either the variable domains VH and VL or the constant domains CH1 and CL are exchanged. The bispecific antibodies are prepared according to the Crossmab technology.

Multispecific antibodies with a domain replacement/exchange in one binding arm (CrossMabVH- VL or CrossMabCH-CL) are described in detail in W02009/080252, W02009/080253 and Schaefer, W. et al, PNAS, 108 (2011 ) 11187-1191 . They clearly reduce the byproducts caused by the mismatch of a light chain against a first antigen with the wrong heavy chain against the second antigen (compared to approaches without such domain exchange).

In a particular aspect, the invention relates to a bispecific antibody comprising a first Fab fragment that specifically binds to PD-1 and a second Fab fragment that specifically binds to LAG3, wherein in one of the Fab fragments the variable domains VL and VH are replaced by each other so that the VH domain is part of the light chain and the VL domain is part of the heavy chain. In a particular aspect, the bispecific antibody is one, wherein in the first Fab fragment comprising the antigen-binding domain that specifically binds to PD-1 the variable domains VL and VH are replaced by each other.

In another aspect, and to further improve correct pairing, the bispecific antibody comprising a first Fab fragment that specifically binds to PD-1 and a second Fab fragment that specifically binds to LAG3, can contain different charged amino acid substitutions (so-called “charged residues”). These modifications are introduced in the crossed or non-crossed CH1 and CL domains. Such modifiactions are described e.g., in WO2015/150447, WO2016/020309 and PCT/EP2016/073408.

In a particular aspect, the invention is concerned with a bispecific antibody comprising a first Fab fragment that specifically binds to PD-1 and a second Fab fragment that specifically binds to LAG3, wherein in one of the Fab fragments in the constant domain CL the amino acid at position 124 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat EU Index), and in the constant domain CH1 the amino acids at positions 147 and 213 are substituted independently by glutamic acid (E) or aspartic acid (D) (numbering according to Kabat EU index). In a particular aspect, the bispecific antibody is one, wherein in the second Fab fragment comprising the antigen-binding domain that specifically binds to TIM3 the constant domain CL the amino acid at position 124 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat EU Index), and in the constant domain CH1 the amino acids at positions 147 and 213 are substituted independently by glutamic acid (E) or aspartic acid (D) (numbering according to Kabat EU index).

In a particular aspect, the invention relates to a bispecific antibody comprising a first Fab fragment that specifically binds to PD-1 and a second Fab fragment that specifically binds to LAG3, wherein in one of CL domains the amino acid at position 123 (EU numbering) has been replaced by arginine (R) and the amino acid at position 124 (EU numbering) has been substituted by lysine (K) and wherein in one of the CH1 domains the amino acids at position 147 (EU numbering) and at position 213 (EU numbering) have been substituted by glutamic acid (E). In a particular aspect, the bispecific antibody is one, wherein in the second Fab fragment comprising the antigen-binding domain that specifically binds to LAG3 the amino acid at position 123 (EU numbering) has been replaced by arginine (R) and the amino acid at position 124 (EU numbering) has been substituted by lysine (K) and wherein in one of the CH1 domains the amino acids at position 147 (EU numbering) and at position 213 (EU numbering) have been substituted by glutamic acid (E).

In a further aspect, the bispecific antibody is a bivalent antibody comprising a) a first light chain and a first heavy chain of an antibody specifically binding to a first antigen, and b) a second light chain and a second heavy chain of an antibody specifically binding to a second antigen, wherein the variable domains VL and VH of the second light chain and the second heavy chain are replaced by each other.

The antibody under a) does not contain a modification as reported under b) and the heavy chain and the light chain under a) are isolated chains.

In the antibody under b) within the light chain the variable light chain domain VL is replaced by the variable heavy chain domain VH of said antibody, and within the heavy chain the variable heavy chain domain VH is replaced by the variable light chain domain VL of said antibody.

In one aspect, (i) in the constant domain CL of the first light chain under a) the amino acid at position 124 (numbering according to Kabat) is substituted by a positively charged amino acid, and wherein in the constant domain CH1 of the first heavy chain under a) the amino acid at position 147 or the amino acid at position 213 (numbering according to Kabat EU index) is substituted by a negatively charged amino acid, or (ii) in the constant domain CL of the second light chain under b) the amino acid at position 124 (numbering according to Kabat) is substituted by a positively charged amino acid, and wherein in the constant domain CH1 of the second heavy chain under b) the amino acid at position 147 or the amino acid at position 213 (numbering according to Kabat EU index) is substituted by a negatively charged amino acid.

In another aspect, (i) in the constant domain CL of the first light chain under a) the amino acid at position 124 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat) (in one preferred embodiment independently by lysine (K) or arginine (R)), and wherein in the constant domain CH1 of the first heavy chain under a) the amino acid at position 147 or the amino acid at position 213 is substituted independently by glutamic acid (E) or aspartic acid (D) (numbering according to Kabat EU index), or (ii) in the constant domain CL of the second light chain under b) the amino acid at position 124 is substituted independently by lysine (K), arginine (R) or histidine (H) (numbering according to Kabat) (in one preferred embodiment independently by lysine (K) or arginine (R)), and wherein in the constant domain CH1 of the second heavy chain under b) the amino acid at position 147 or the amino acid at position 213 is substituted independently by glutamic acid (E) or aspartic acid (D) (numbering according to Kabat EU index).

In one aspect, in the constant domain CL of the second heavy chain the amino acids at position 124 and 123 are substituted by K (numbering according to Kabat EU index).

In one aspect, in the constant domain CL of the second heavy chain the amino acid at position 123 is substituted by R and the amino acid as position 124 is substituted by K (numbering according to Kabat EU index). In one aspect, in the constant domain CH1 of the second light chain the amino acids at position 147 and 213 are substituted by E (numbering according to EU index of Kabat).

In one aspect, in the constant domain CL of the first light chain the amino acids at position 124 and 123 are substituted by K, and in the constant domain CH1 of the first heavy chain the amino acids at position 147 and 213 are substituted by E (numbering according to Kabat EU index).

In one aspect, in the constant domain CL of the first light chain the amino acid at position 123 is substituted by R and the amino acid at position 124 is substituted by K, and in the constant domain CH1 of the first heavy chain the amino acids at position 147 and 213 are both substituted by E (numbering according to Kabat EU index).

In one aspect, in the constant domain CL of the second heavy chain the amino acids at position 124 and 123 are substituted by K, and wherein in the constant domain CH1 of the second light chain the amino acids at position 147 and 213 are substituted by E, and in the variable domain VL of the first light chain the amino acid at position 38 is substituted by K, in the variable domain VH of the first heavy chain the amino acid at position 39 is substituted by E, in the variable domain VL of the second heavy chain the amino acid at position 38 is substituted by K, and in the variable domain VH of the second light chain the amino acid at position 39 is substituted by E (numbering according to Kabat EU index).

In one aspect, the bispecific antibody is a bivalent antibody comprising a) a first light chain and a first heavy chain of an antibody specifically binding to a first antigen, and b) a second light chain and a second heavy chain of an antibody specifically binding to a second antigen, wherein the variable domains VL and VH of the second light chain and the second heavy chain are replaced by each other, and wherein the constant domains CL and CH1 of the second light chain and the second heavy chain are replaced by each other.

The antibody under a) does not contain a modification as reported under b) and the heavy chain and the light chain und a) are isolated chains. In the antibody under b) within the light chain the variable light chain domain VL is replaced by the variable heavy chain domain VH of said antibody, and the constant light chain domain CL is replaced by the constant heavy chain domain CH1 of said antibody; and within the heavy chain the variable heavy chain domain VH is replaced by the variable light chain domain VL of said antibody, and the constant heavy chain domain CH1 is replaced by the constant light chain domain CL of said antibody.

In one aspect, the bispecific antibody is a bivalent antibody comprising a) a first light chain and a first heavy chain of an antibody specifically binding to a first antigen, and b) a second light chain and a second heavy chain of an antibody specifically binding to a second antigen, wherein the constant domains CL and CH1 of the second light chain and the second heavy chain are replaced by each other.

The antibody under a) does not contain a modification as reported under b) and the heavy chain and the light chain under a) are isolated chains. In the antibody under b) within the light chain the constant light chain domain CL is replaced by the constant heavy chain domain CH1 of said antibody; and within the heavy chain the constant heavy chain domain CH1 is replaced by the constant light chain domain CL of said antibody.

In one aspect, the bispecific antibody is a bispecific antibody comprising a) a full-length antibody specifically binding to a first antigen and consisting of two antibody heavy chains and two antibody light chains, and b) one, two, three or four single chain Fab fragments specifically binding to a second antigen, wherein said single chain Fab fragments under b) are fused to said full-length antibody under a) via a peptide linker at the C- or N- terminus of the heavy or light chain of said full length antibody.

In one aspect, one or two identical single chain Fab fragments binding to a second antigen are fused to the full-length antibody via a peptide linker at the C terminus of the heavy or light chains of said full-length antibody.

In one aspect, one or two identical single chain Fab (scFab) fragments binding to a second antigen are fused to the full-length antibody via a peptide linker at the C terminus of the heavy chains of said full-length antibody.

In one aspect, one or two identical single chain Fab (scFab) fragments binding to a second antigen are fused to the full-length antibody via a peptide linker at the C terminus of the light chains of said full-length antibody.

In one aspect, two identical single chain Fab (scFab) fragments binding to a second antigen are fused to the full-length antibody via a peptide linker at the C-terminus of each heavy or light chain of said full-length antibody.

In one aspect, two identical single chain Fab (scFab) fragments binding to a second antigen are fused to the full-length antibody via a peptide linker at the C-terminus of each heavy chain of said full- length antibody.

In one aspect, two identical single chain Fab (scFab) fragments binding to a second antigen are fused to the full-length antibody via a peptide linker at the C-terminus of each light chain of said full-length antibody.

In one aspect, the bispecific antibody is a trivalent antibody comprising a) a full-length antibody specifically binding to a first antigen and consisting of two antibody heavy chains and two antibody light chains, b) a first polypeptide consisting of ba) an antibody heavy chain variable domain (VH), or bb) an antibody heavy chain variable domain (VH) and an antibody constant domain 1 (CH1 ), wherein said first polypeptide is fused with the N-terminus of its VH domain via a peptidic linker to the C-terminus of one of the two heavy chains of said full-length antibody, c) a second polypeptide consisting of ca) an antibody light chain variable domain (VL), or cb) an antibody light chain variable domain (VL) and an antibody light chain constant domain (CL), wherein said second polypeptide is fused with the N-terminus of the VL domain via a peptide linker to the C-terminus of the other of the two heavy chains of said full-length antibody, and wherein the antibody heavy chain variable domain (VH) of the first polypeptide and the antibody light chain variable domain (VL) of the second polypeptide together form an antigen-binding domain specifically binding to a second antigen. In one aspect, the antibody heavy chain variable domain (VH) of the polypeptide under b) and the antibody light chain variable domain (VL) of the polypeptide under c) are linked and stabilized via an interchain disulfide bridge by introduction of a disulfide bond between the following positions:

(i) heavy chain variable domain position 44 to light chain variable domain position 100, or

(ii) heavy chain variable domain position 105 to light chain variable domain position 43, or

(iii) heavy chain variable domain position 101 to light chain variable domain position 100 (numbering always according to Kabat EU index).

Techniques to introduce unnatural disulfide bridges for stabilization are described, e.g., in WO 94/029350, Rajagopal, V., et al., Prot. Eng. (1997) 1453-1459; Kobayashi, H., et al., Nucl. Med. Biol. 25 (1998) 387-393; and Schmidt, M., et al., Oncogene 18 (1999) 1711 -1721 . In one embodiment the optional disulfide bond between the variable domains of the polypeptides under b) and c) is between heavy chain variable domain position 44 and light chain variable domain position 100. In one embodiment the optional disulfide bond between the variable domains of the polypeptides under b) and c) is between heavy chain variable domain position 105 and light chain variable domain position 43 (numbering always according to Kabat). In one embodiment a trivalent, bispecific antibody without said optional disulfide stabilization between the variable domains VH and VL of the single chain Fab fragments is preferred.

In one aspect, the bispecific antibody is a trispecific or tetraspecific antibody, comprising a) a first light chain and a first heavy chain of a full-length antibody which specifically binds to a first antigen, and b) a second (modified) light chain and a second (modified) heavy chain of a full-length antibody which specifically binds to a second antigen, wherein the variable domains VL and VH are replaced by each other, and/or wherein the constant domains CL and CH1 are replaced by each other, and c) wherein one to four antigen-binding domains which specifically bind to one or two further antigens (i.e. , to a third and/or fourth antigen) are fused via a peptide linker to the C- or N-terminus of the light chains or heavy chains of a) and/or b).

The antibody under a) does not contain a modification as reported under b) and the heavy chain and the light chain und a) are isolated chains.

In one aspect, the trispecific or tetraspecific antibody comprises under c) one or two antigenbinding domains which specifically bind to one or two further antigens.

In one aspect, the antigen-binding domains are selected from the group of a scFv fragment and a scFab fragment.

In one aspect, the antigen-binding domains are scFv fragments.

In one aspect, the antigen-binding domains are scFab fragments.

In one aspect, the antigen-binding domains are fused to the C-terminus of the heavy chains of a) and/or b).

In one aspect, the trispecific or tetraspecific antibody comprises under c) one or two antigenbinding domains which specifically bind to one further antigen.

In one aspect, the trispecific or tetraspecific antibody comprises under c) two identical antigenbinding domains which specifically bind to a third antigen. In one preferred embodiment such two identical antigen-binding domains are fused both via the same peptidic linker to the C-terminus of the heavy chains of a) and b). In one preferred embodiment the two identical antigen-binding domains are either a scFv fragment or a scFab fragment.

In one aspect, the trispecific or tetraspecific antibody comprises under c) two antigen-binding domains which specifically bind to a third and a fourth antigen. In one embodiment said two antigenbinding domains are fused both via the same peptide connector to the C-terminus of the heavy chains of a) and b). In one preferred embodiment said two antigen-binding domains are either a scFv fragment or a scFab fragment.

In one aspect, the bispecific antibody is a bispecific, tetravalent antibody comprising a) two light chains and two heavy chains of an antibody, which specifically bind to a first antigen (and comprise two Fab fragments), b) two additional Fab fragments of an antibody, which specifically bind to a second antigen, wherein said additional Fab fragments are fused both via a peptidic linker either to the C- or N-termini of the heavy chains of a), and wherein in the Fab fragments the following modifications were performed

(i) in both Fab fragments of a), or in both Fab fragments of b), the variable domains VL and VH are replaced by each other, and/or the constant domains CL and CH1 are replaced by each other, or

(ii) in both Fab fragments of a) the variable domains VL and VH are replaced by each other, and the constant domains CL and CH1 are replaced by each other, and in both Fab fragments of b) the variable domains VL and VH are replaced by each other, or the constant domains CL and CH1 are replaced by each other, or

(iii) in both Fab fragments of a) the variable domains VL and VH are replaced by each other, or the constant domains CL and CH1 are replaced by each other, and in both Fab fragments of b) the variable domains VL and VH are replaced by each other, and the constant domains CL and CH1 are replaced by each other, or

(iv) in both Fab fragments of a) the variable domains VL and VH are replaced by each other, and in both Fab fragments of b) the constant domains CL and CH1 are replaced by each other, or

(v) in both Fab fragments of a) the constant domains CL and CH1 are replaced by each other, and in both Fab fragments of b) the variable domains VL and VH are replaced by each other.

In one aspect, said additional Fab fragments are fused both via a peptidic linker either to the C- termini of the heavy chains of a), or to the N-termini of the heavy chains of a).

In one aspect, said additional Fab fragments are fused both via a peptidic linker to the C-termini of the heavy chains of a).

In one aspect, said additional Fab fragments are fused both via a peptide linker to the N-termini of the heavy chains of a).

In one aspect, in the Fab fragments the following modifications are performed: in both Fab fragments of a), or in both Fab fragments of b), the variable domains VL and VH are replaced by each other, and/or the constant domains CL and CH1 are replaced by each other.

In one aspect, the bispecific antibody is a tetravalent antibody comprising: a) a (modified) heavy chain of a first antibody, which specifically binds to a first antigen and comprises a first VH-CH1 domain pair, wherein to the C terminus of said heavy chain the N-terminus of a second VH-CH1 domain pair of said first antibody is fused via a peptide linker, b) two light chains of said first antibody of a), c) a (modified) heavy chain of a second antibody, which specifically binds to a second antigen and comprises a first VH-CL domain pair, wherein to the C-terminus of said heavy chain the N-terminus of a second VH-CL domain pair of said second antibody is fused via a peptide linker, and d) two (modified) light chains of said second antibody of c), each comprising a CL-CH1 domain pair.

In one aspect, the bispecific antibody comprises a) the heavy chain and the light chain of a first full-length antibody that specifically binds to a first antigen, and b) the heavy chain and the light chain of a second full-length antibody that specifically binds to a second antigen, wherein the N-terminus of the heavy chain is connected to the C-terminus of the light chain via a peptide linker.

The antibody under a) does not contain a modification as reported under b) and the heavy chain and the light chain are isolated chains.

In one aspect, the bispecific antibody comprises a) a full-length antibody specifically binding to a first antigen and consisting of two antibody heavy chains and two antibody light chains, and b) an Fv fragment specifically binding to a second antigen comprising a VH2 domain and a VL2 domain, wherein both domains are connected to each other via a disulfide bridge, wherein only either the VH2 domain or the VL2 domain is fused via a peptide linker to the heavy or light chain of the full-length antibody specifically binding to a first antigen.

In the bispecific antibody the heavy chains and the light chains under a) are isolated chains.

In one aspect, the other of the VH2 domain or the VL2 domain is not fused via a peptide linker to the heavy or light chain of the full-length antibody specifically binding to a first antigen.

In all aspects as reported herein the first light chain comprises a VL domain and a CL domain and the first heavy chain comprises a VH domain, a CH1 domain, a hinge region, a CH2 domain and a CH3 domain.

In one aspect, the bispecific antibody is a trivalent antibody comprising a) two Fab fragments that specifically binds to a first antigen, b) one CrossFab fragment that specifically binds to a second antigen in which the CH1 and the CL domain are exchanged for each other, c) one Fc-region comprising a first Fc-region heavy chain and a second Fc region heavy chain, wherein the C-terminus of CH1 domains of the two Fab fragments are connected to the N-terminus of the heavy chain Fc-region polypeptides, and wherein the C-terminus of the CL domain of the CrossFab fragment is connected to the N-terminus of the VH domain of one of the Fab fragments.

In one aspect, the bispecific antibody is a trivalent antibody comprising a) two Fab fragments that specifically binds to a first antigen, b) one CrossFab fragment that specifically binds to a second antigen in which the CH1 and the CL domain are exchanged for each other, c) one Fc-region comprising a first Fc-region heavy chain and a second Fc region heavy chain, wherein the C-terminus of CH1 domain of the first Fab fragment is connected to the N-terminus of one of the heavy chain Fc-region polypeptides and the C-terminus of the CL-domain of the CrossFab fragment is connected to the N-terminus of the other heavy chain Fc-region polypeptide, and wherein the C-terminus of the CH1 domain of the second Fab fragment is connected to the N-terminus of the VH domain of the first Fab fragment or to the N-terminus of the VH domain of the CrossFab fragment.

In one aspect, the bispecific antibody comprises a) a full-length antibody specifically binding to a first antigen and consisting of two antibody heavy chains and two antibody light chains, and b) a Fab fragment specifically binding to a second antigen comprising a VH2 domain and a VL2 domain comprising a heavy chain fragment and a light chain fragment, wherein within the light chain fragment the variable light chain domain VL2 is replaced by the variable heavy chain domain VH2 of said antibody, and within the heavy chain fragment the variable heavy chain domain VH2 is replaced by the variable light chain domain VL2 of said antibody wherein the heavy chain Fab fragment is inserted between the CH1 domain of one of the heavy chains of the full-length antibody and the respective Fc-region of the full-length antibody, and the N- terminus of the light chain Fab fragment is conjugated to the C-terminus of the light chain of the full- length antibody that is paired with the heavy chain of the full-length antibody into which the heavy chain Fab fragment has been inserted.

In one aspect, the bispecific antibody comprises a) a full-length antibody specifically binding to a first antigen and consisting of two antibody heavy chains and two antibody light chains, and b) a Fab fragment specifically binding to a second antigen comprising a VH2 domain and a VL2 domain comprising a heavy chain fragment and a light chain fragment, wherein within the light chain fragment the variable light chain domain VL2 is replaced by the variable heavy chain domain VH2 of said antibody, and within the heavy chain fragment the variable heavy chain domain VH2 is replaced by the variable light chain domain VL2 of said antibody and wherein the C-terminus of the heavy chain fragment of the Fab fragment is conjugated to the N-terminus of one of the heavy chains of the full-length antibody and the C-terminus of the light chain fragment of the Fab fragment is conjugated to the N-terminus of the light chain of the full-length antibody that pairs with the heavy chain of the full-length antibody to which the heavy chain fragment of the Fab fragment is conjugated.

B. Dosing of bispecific antibodies that bind to PD-1 and LAG3

For the prevention or treatment of disease, the appropriate dosage of a bispecific antibodies comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3 of the invention (when used alone or in combination with one or more other additional therapeutic agents) will depend on the type of disease to be treated, the route of administration, the body weight of the subject, the type of fusion protein, the severity and course of the disease, whether the bispecific antibody is administered for preventive or therapeutic purposes, previous or concurrent therapeutic interventions, the subject's clinical history and response to the fusion protein, and the discretion of the attending physician. The practitioner responsible for administration will, in any event, determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject. Various dosing schedules including but not limited to single or multiple administrations over various time-points, bolus administration, and pulse infusion are contemplated herein.

The bispecific antibody comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3 as defined herein is suitably administered to the subject at one time or over a series of treatments. Depending on the type and severity of the disease, about 1 pg/kg to 15 mg/kg (e.g., 0.1 mg/kg - 10 mg/kg) of the bispecific antibody can be an initial candidate dosage for administration to the subject, whether, for example, by one or more separate administrations, or by continuous infusion. One typical daily dosage might range from about 1 pg/kg to 100 mg/kg or more, depending on the factors mentioned above. For repeated administrations over several days or longer, depending on the condition, the treatment would generally be sustained until a desired suppression of disease symptoms occurs. One exemplary dosage of the bispecific antibody would be in the range from about 0.005 mg/kg to about 10 mg/kg. In other examples, a dose may also comprise from about 1 pg/kg body weight, about 5 pg/kg body weight, about 10 pg/kg body weight, about 50 pg/kg body weight, about 100 pg/kg body weight, about 200 pg/kg body weight, about 350 pg/kg body weight, about 500 pg/kg body weight, about 1 mg/kg body weight, about 5 mg/kg body weight, about 10 mg/kg body weight, about 50 mg/kg body weight, about 100 mg/kg body weight, about 200 mg/kg body weight, about 350 mg/kg body weight, about 500 mg/kg body weight, to about 1000 mg/kg body weight or more per administration, and any range derivable therein. In examples of a derivable range from the numbers listed herein, a range of about 5 mg/kg body weight to about 100 mg/kg body weight, about 5 pg/kg body weight to about 500 mg/kg body weight etc., can be administered, based on the numbers described above. Thus, one or more doses of about 0.5 mg/kg, 2.0 mg/kg, 5.0 mg/kg or 10 mg/kg (or any combination thereof) may be administered to the subject. Such doses may be administered intermittently, e.g. every week or every three weeks (e.g. such that the subject receives from about two to about twenty, or e.g. about six doses of the fusion protein). An initial higher loading dose, followed by one or more lower doses may be administered. However, other dosage regimens may be useful. The progress of this therapy is easily monitored by conventional techniques and assays.

In one aspect, the bispecific antibody targeting PD-1 and LAG3 is administered to the subject at a fixed dose of about 300 mg, of about 500 mg, of about 600 mg, of about 700 mg, of about 800 mg, of about 900 mg, of about 1000 mg, of about 1100 mg or of about 1200 mg every three weeks (Q3W) e.g., at a fixed dose administered on Day 1 (± 1 day) of a three-week dosing cycle). In one particular aspect, the bispecific antibody targeting PD-1 and LAG3 is administered to the subject at a fixed dose of about 600 mg every three weeks (Q3W), e.g., at a fixed dose of 600 mg Q3W (e.g., administered on Day 1 (± 1 day) of a three-week dosing cycle). In particular, the bispecific antibody targeting PD-1 and LAG3 is administered to the subject at a fixed dose of about 600 mg every three weeks (Q3W) on Day 1 of the three-week dosing cycle.

In another aspect, the bispecific antibody targeting PD-1 and LAG3 is administered to the subject at a fixed dose of about 1200 mg every three weeks, e.g., at a fixed dose of 1200 mg Q3W.

In another aspect, the bispecific antibody targeting PD-1 and LAG3 is administered to the subject at a fixed dose of about 2100 mg every two weeks (Q2W), e.g., at a fixed dose of 2100 mg Q2W.

C. Dosing of paclitaxel

Therapeutically effective amounts of various chemotherapeutic agents, in particular taxanes (e.g., paclitaxel), are known in the art and contemplated in the present invention. In particular instances, paclitaxel is administered intravenously at a dose of 200 mg/m² once every three weeks. In one instance, the starting dose level of paclitaxel in the study is 200 mg/m² administered intravenously over 3 hours once every three weeks.

D. Dosing of pemetrexed

Therapeutically effective amounts of various chemotherapeutic agents, in particular antimetabolites (e.g., pemetrexed), are known in the art and contemplated in the present invention. In particular instances, pemetrexed is administered intravenously at a dose of 500 mg/m² once every three weeks. In one instance, the starting dose level of pemetrexed in the study is 500 mg/m² administered intravenously once every three weeks.

E. Dosing of carboplatin

Therapeutically effective amounts of various chemotherapeutic agents, in particular platinumbased chemotherapeutic agents (e.g., carboplatin), are known in the art and contemplated in the present invention. In particular instances, carboplatin is administered intravenously at a targeted area under the concentration-time curve (AUC) of 5 mg/mL • min every three weeks. In one instance, the starting dose level of carboplatin in the study is 100 mg/m² administered intravenously at a targeted AUC of 5 mg/mL • min every three weeks.

F. Dosing of nab-paclitaxel

Therapeutically effective amounts of various chemotherapeutic agents, in particular taxanes (e.g., paclitaxel, e.g., nab-paclitaxel), are known in the art and contemplated in the present invention. In particular instances, nab-paclitaxel is administered intravenously at a dose of 100 mg/m² once a week for three weeks followed by 1 week off. Doses of nab-paclitaxel should not be administered more frequently than every 7 days. In one instance, the starting dose level of nab-paclitaxel in the study is 100 mg/m² administered intravenously over 30 minutes weekly on a repeating schedule of 3 weeks on followed by 1 week off. V. Pharmaceutical Compositions and Formulations

Also provided herein are pharmaceutical compositions and formulations comprising a bispecific antibody targeting PD-1 and LAG3 and, optionally, a pharmaceutically acceptable carrier. The disclosure also provides pharmaceutical compositions and formulations comprising a bispecific antibody targeting PD-1 and LAG3 and one or more chemotherapeutic agents (e.g., (a) one or both of pemetrexed and carboplatin, (b) one or both of paclitaxel and carboplatin, or (c) nab-paclitaxel), and optionally, a pharmaceutically acceptable carrier. Pharmaceutical compositions and formulations of a bispecific antibody targeting PD-1 and LAG3 and/or other agents described herein (e.g., one or more chemotherapeutic agents, e.g., (a) one or both of pemetrexed and carboplatin, (b) one or both of paclitaxel and carboplatin, or (c) nab-paclitaxel) can be prepared by mixing the agent or agents having the desired degree of purity with one or more optional pharmaceutically acceptable carriers (Remington’s Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions.

Pharmaceutical compositions and formulations as described herein can be prepared by mixing the active ingredients (e.g., a bispecific antibody targeting PD-1 and LAG3 and/or one or more chemotherapeutic agents (e.g., (a) one or both of pemetrexed and carboplatin, (b) one or both of paclitaxel and carboplatin, or (c) nab-paclitaxel)) having the desired degree of purity with one or more optional pharmaceutically acceptable carriers (see, e.g., Flemington’s Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)), e.g., in the form of lyophilized formulations or aqueous solutions.

Pharmaceutically acceptable carriers are generally nontoxic to recipients at the dosages and concentrations employed, and include, but are not limited to: buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionic surfactants such as polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers herein further include interstitial drug dispersion agents such as soluble neutral-active hyaluronidase glycoproteins (sHASEGP), for example, human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20 (HYLENEX®, Baxter International, Inc.). Certain exemplary sHASEGPs and methods of use, including rHuPH20, are described in U.S. Patent Publication Nos. 2005/0260186 and 2006/0104968. In one aspect, a sHASEGP is combined with one or more additional glycosaminoglycanases such as chondroitinases.

Exemplary lyophilized antibody formulations are described in U.S. Patent No. 6,267,958. Aqueous antibody formulations include those described in U.S. Patent No. 6,171 ,586 and W02006/044908, the latter formulations including a histidine-acetate buffer. The formulation herein may also contain more than one active ingredient as necessary for the particular indication being treated, preferably those with complementary activities that do not adversely affect each other. For example, it may be desirable to further provide an additional therapeutic agent (e.g., a chemotherapeutic agent, a cytotoxic agent, a growth inhibitory agent, and/or an anti-hormonal agent, such as those recited herein above). Such active ingredients are suitably present in combination in amounts that are effective for the purpose intended.

Active ingredients may be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methyl methacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Flemington’s Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, for example, films, or microcapsules.

The formulations to be used for in vivo administration are generally sterile. Sterility may be readily accomplished, e.g., by filtration through sterile filtration membranes.

VI. Articles of Manufacture or Kits

A. Kits comprising a bispecific antibody targeting PD- 1 and LAG3 and one or more chemotherapeutic agents

In another aspect, provided herein is an article of manufacture or a kit comprising a bispecific antibody targeting PD-1 and LAG3 and one or more chemotherapeutic agents (e.g., (a) one or both of pemetrexed and carboplatin, (b) one or both of paclitaxel and carboplatin, or (c) nab-paclitaxel). In some instances, the article of manufacture or kit further comprises a package insert comprising instructions for using the chemotherapeutic agent (e.g., (a) one or both of pemetrexed and carboplatin, (b) one or both of paclitaxel and carboplatin, or (c) nab-paclitaxel) in combination with the bispecific antibody targeting PD-1 and LAG3 to treat or delay progression of a cancer (e.g., an NSCLC (e.g., a squamous or non-squamous NSCLC, e.g., a Stage IIIB/IIIC or Stage IV squamous or non-squamous NSCLC) or a TNBC (e.g., a locally advanced, unresectable or metastatic TNBC)) in a subject. Any of the bispecific antibodies targeting PD-1 and LAG3 and/or chemotherapeutic agents described herein may be included in the article of manufacture or kits.

In another embodiment of the invention, a kit is provided comprising a bispecific antibody targeting PD-1 and LAG3 for use in combination with a chemotherapeutic agent (e.g., one or both of pemetrexed and carboplatin) for treating a subject having a cancer (e.g., a non-squamous NSCLC, e.g., a Stage IIIB/IIIC or Stage IV non-squamous NSCLC) according to any of the methods described herein. In some instances, the kit further comprises the chemotherapeutic agent (e.g., one or both of pemetrexed and carboplatin). In some instances, the article of manufacture or kit further comprises a package insert comprising instructions for using the bispecific antibody targeting PD-1 and LAG3 in combination with the chemotherapeutic agent (e.g., one or both of pemetrexed and carboplatin) to treat or delay progression of a cancer (e.g., a non-squamous NSCLC, e.g., a Stage IIIB/IIIC or Stage IV non-squamous NSCLC) in a subject.

In another embodiment of the invention, a kit is provided comprising a bispecific antibody targeting PD-1 and LAG3 for use in combination with a chemotherapeutic agent (e.g., one or both of paclitaxel and carboplatin) for treating a subject having a cancer (e.g., a squamous NSCLC, e.g., a Stage IIIB/IIIC or Stage IV squamous NSCLC) according to any of the methods described herein. In some instances, the kit further comprises the chemotherapeutic agent (e.g., one or both of paclitaxel and carboplatin). In some instances, the article of manufacture or kit further comprises a package insert comprising instructions for using the bispecific antibody targeting PD-1 and LAG3 in combination with the chemotherapeutic agent (e.g., one or both of paclitaxel and carboplatin) to treat or delay progression of a cancer (e.g., a squamous NSCLC, e.g., a Stage IIIB/IIIC or Stage IV squamous NSCLC) in a subject.

In another embodiment of the invention, a kit is provided comprising a bispecific antibody targeting PD-1 and LAG3 for use in combination with a chemotherapeutic agent (e.g., nab-paclitaxel) for treating a subject having a cancer (e.g., a TNBC, e.g., a locally advanced, unresectable or metastatic TNBC) according to any of the methods described herein. In some instances, the kit further comprises the chemotherapeutic agent (e.g., nab-paclitaxel). In some instances, the article of manufacture or kit further comprises a package insert comprising instructions for using the bispecific antibody targeting PD- 1 and LAG3 in combination with the chemotherapeutic agent (e.g., nab-paclitaxel) to treat or delay progression of a cancer (e.g., a TNBC, e.g., a locally advanced, unresectable or metastatic TNBC) in a subject.

In some instances, the bispecific antibody targeting PD-1 and LAG3 and the one or more chemotherapeutic agents (e.g., (a) one or both of pemetrexed and carboplatin, (b) one or both of paclitaxel and carboplatin, or (c) nab-paclitaxel) are in the same container or separate containers. Suitable containers include, for example, bottles, vials, bags and syringes. The container may be formed from a variety of materials such as glass, plastic (such as polyvinyl chloride or polyolefin), or metal alloy (such as stainless steel or hastelloy). In some instances, the container holds the formulation and the label on, or associated with, the container may indicate directions for use. The article of manufacture or kit may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, syringes, and package inserts with instructions for use. In some instances, the article of manufacture further includes one or more of another agent (e.g., an additional chemotherapeutic agent or anti-neoplastic agent). Suitable containers for the one or more agents include, for example, bottles, vials, bags and syringes.

Any of the bispecific antibodies targeting PD-1 and LAG3 and/or chemotherapeutic agents (e.g., pemetrexed, pacltitaxel, and/or carboplatin, or nab-paclitaxel) described herein may be included in the article of manufacture or kits. Any of the articles of manufacture or kits may include instructions to administer a bispecific antibody targeting PD-1 and LAG3 and/or one or more chemotherapeutic agents (e.g., (a) one or both of pemetrexed and carboplatin, (b) one or both of paclitaxel and carboplatin, or (c) nab-paclitaxel) to a subject in accordance with any of the methods described herein, e.g., any of the methods set forth in Section II above. VII. EXAMPLES

Example 1 : A Phase II, Randomized, Multicenter, Double-Blind, Controlled Study Of RO7247669 Plus Platinum-Based Chemotherapy Versus Pembrolizumab Plus Platinum-Based Chemotherapy in Patients with Previously Untreated Locally Advanced Or Metastatic Non-Small Cell Lung Cancer

A. Overview of Study Design

CO44194 is a randomized, Phase II, global, multicenter, double-blind study designed to evaluate the efficacy, safety, and pharmacokinetics of RO7247669 in combination with platinum-based chemotherapy compared with pembrolizumab plus platinum-based chemotherapy in patients with previously untreated, locally advanced unresectable (Stage IIIB/IIIC) or metastatic (Stage IV) non-small cell lung cancer (NSCLC) who are not eligible for curative surgery and/or definitive chemoradiotherapy.

Approximately 180 patients are randomized in the study in a 1 :1 ratio to receive either RO7247669 plus platinum-based chemotherapy (Arm A) or pembrolizumab plus platinum-based chemotherapy (Arm B), as follows:

Arm A (n = ~90): RO7247669 plus platinum-based chemotherapy.

• Participants with non-squamous (NSQ) NSCLC will receive induction treatment with blinded RO7247669 in combination with pemetrexed and carboplatin, all on Day 1 every 3 weeks (Q3W) for four 21 -day cycles, followed by Q3W maintenance therapy with blinded RO7247669 together with pemetrexed until disease progression or treatment discontinuation.

• Participants with squamous (SQ) NSCLC will receive blinded RO7247669 in combination with paclitaxel and carboplatin, all on Day 1 Q3W for four 21 -day cycles, followed by blinded RO7247669 (on Day 1 ) Q3W until disease progression or treatment discontinuation.

Arm B (n = ~90): Pembrolizumab plus platinum-based chemotherapy.

• Participants with NSQ NSCLC will receive induction treatment with blinded pembrolizumab in combination with pemetrexed and carboplatin, all on Day 1 Q3W for four 21 -day cycles, followed by a maintenance therapy with blinded pembrolizumab together with pemetrexed Q3W until disease progression or treatment discontinuation.

• Participants with SQ NSCLC will receive blinded pembrolizumab in combination with paclitaxel and carboplatin, all on Day 1 Q3W for four 21 -day cycles, followed by blinded pembrolizumab (on Day 1 ) Q3W until disease progression or treatment discontinuation.

Treatment continues until disease progression per RECIST v1 .1 . The total duration of study participation for each individual is expected to range from 1 day to up to 58 months.

In this protocol, "study treatment" refers to the combination of treatments assigned to patients as part of this study (i.e., RO7247669 or pembrolizumab in combination with pemetrexed and carboplatin or paclitaxel and carboplatin).

Several key aspects of the study design and study population are summarized in Table 3. An overview of the study is presented in Fig. 1 . Table 3. Summary of CO44194 study

The objectives and endpoitns of the study are presented in Table 4. Table 4. Objectives and Endpoints

Blinded RO7247669 and Blinded Pembrolizumab

Participants receive blinded RO7247669 (600 mg every three weeks (Q3W)) or blinded pembrolizumab (200 mg Q3W) by IV infusion. Administration of study treatment is performed in a monitored setting where there is immediate access to trained personnel and adequate equipment and medicine to manage potentially serious reactions. The 600-mg dose of RO7247669 Q3W and the 200- mg dose of pembrolizumab Q3W remain the same throughout the study.

The initial dose of RO7247669 or pembrolizumab is delivered over 60 (± 15) minutes by IV infusion. If the 60-minute infusion is tolerated without infusion-associated adverse events (fever or chills), the second infusion may be delivered over 30 (± 10) minutes. If the 30-minute infusion is well tolerated, all subsequent infusions may be delivered over 30 (± 10) minutes.

Pemetrexed, Paclitaxel, and Carboplatin

Paclitaxel, pemetrexed, and carboplatin are administered to participants as outlined in Table 5. Table 5. Treatment Regimen for Pemetrexed, Paclitaxel, and Carboplatin

Paclitaxel

Paclitaxel 200 mg/m² is administered as an IV infusion to participants over 3 hours Q3W for four cycles as per local practice and labels. All participants are premedicated with oral or an IV steroid and antihistamines according to the approved product label and/or standard practice. Additional premedications are administered as per standard practice. Paclitaxel is completely administered before initiating carboplatin dose.

Pemetrexed

Pemetrexed 500 mg/m² is administered to participants as an IV infusion over 10 minutes Q3W until progression or unacceptable toxicity.

All participants receive the appropriate supplementation with vitamin B12 and folic acid and corticosteroid prophylaxis as listed below (or as per local label):

• Folic acid 350-1000 pg orally (PO): Participants must take at least five doses of folic acid during the 7 days preceding the first dose of pemetrexed, and folic acid dosing must continue during the full course of therapy and for 21 days after the final dose of pemetrexed.

• Vitamin B12 1000 pg intramuscular (IM) injection: Participants receive an IM injection the week preceding the first dose of pemetrexed and once every three cycles thereafter. Subsequent vitamin B12 injections may be given the same day as pemetrexed administration.

• Anti-emetic prophylaxis with dexamethasone 4 mg (or equivalent) PO twice per day: Participants should take dexamethasone the day before, the day of, and the day after pemetrexed administration. Higher or additional doses are permitted for anti-emetic prophylaxis during Cycles 1 -4 but are not to exceed doses per the Multinational Association of Supportive Care and European Society of Medical Oncology.

Carboplatin

Carboplatin area under the concentration-time curve (AUC) 5 mg/mL • min: Participants receive carboplatin as an IV infusion over 30-60 minutes Q3W for four cycles immediately after paclitaxel or pemetrexed as per local practice and labels. The dose of carboplatin is calculated using Calvert formula (see below) and should not exceed 750 mg. Calvert Formula:

Total dose (in milligrams [mg]) = (target AUC) x (creatine clearance [CrCI}+25).

The estimated glomerular filtration rate used in the Calvert formula should not exceed 125 mL/min. Maximum carboplatin dose (mg) = target AUC 5 (mg/mL • min) x(125 + 25) = 5x 150 mL/min = 750 mg.

Benefit-Risk Assessment

Patients with advanced or metastatic solid tumors present a great unmet need. Benefit from cancer immunotherapy with CPI monoclonal antibodies, such as those targeting PD-1/ PD-L1 , is predominantly observed in a subset of patients with inflamed tumor phenotypes. However, response is not guaranteed even in this patient subset owing to either primary or acquired resistance mechanisms. Upregulated LAG3 expression on T cells is associated with T-cell dysfunction, potentially resulting in adaptive resistance to anti-PD-1/PD-L1 therapies (Sharma et al., Cell, 168: 707-723, 2017). Therefore, LAG3 blockade of tumor-infiltrating lymphocytes (TILs) may overcome or prevent resistance mechanisms to anti-PD-1/PD-L1 and help restore or increase T-cell proliferation and cytotoxic effector functions.

RO7247669 concurrently targets two dominant immune-checkpoint receptors, PD-1 and LAG3. Such targeting may serve to overcome resistance by means of synergic ligand blockade and subsequent re-invigoration of TILs, regardless of T-regulatory cells, and potentially delay or prevent the development of LAG3-mediated adaptive resistance mechanisms.

Up to the clinical cut-off date of 1 March 2022, RO7247669 has been tolerated at doses of up to 2100 mg every 2 weeks (Q2W); adverse events (AEs) have been manageable, and the safety profile is observed to be consistent across different solid tumor indications including NSCLC as well as with approved PD-1 directed antibodies.

Relevant efficacy and safety data up to the data cut-off date of 1 March 2022 for RO724766 are currently available from Study NP41300, a Phase I study in patients with advanced and/or metastatic solid tumors.

In the dose-escalation part of the study NP41300, the disease control rate (DCR) was 51 .4% (18 of 35 evaluable participants) and the objective response rate (ORR) was 17.1% (6 of 35 participants). Responses were observed in both CPI naive and CPI-experienced participants across various tumor types, at 600 mg Q2W and 2100 mg Q2W. In the second part of the study, the DCR among patients of the study treated at 2100 mg Q2W was 48.3% (28/58) and the ORR was 5.2% (3/58). Within patients treated with 600 mg Q2W, DCR was 40% (4/10), and ORR was 10% (1/10). Among patients treated with 600 mg Q3W, DCR was 28.6% (2/7) and ORR was 14.3% (1/7).

A total of 27 participants with NSCLC have been evaluated for efficacy in Study NP41300 as of 01 March 2022. Of these, 25 were second line/third line CPI experienced and 2 were CPI naive, but had received other treatments. In this population, DCR was 51 .9%, with 2/27 NSCLC patients experiencing a cPR (ORR 7.4%). The first responder was a 4th line CPI naive participant, treated with 600 mg Q2W. The patient showed a duration of response of 19.1 months and a progression-free survival (PFS) of 22.3 months at the data cut off, and the response is still ongoing. The second responder was a CPI experienced participant, treated with 600 mg Q2W, with a duration of response (still ongoing at the data cut-off date) of 1 .9 months. Both participants are still receiving treatment in the study. A total of 31 participants with NSCLC were safety evaluable in the study NP41300. The majority of the events reported were mild to moderate in severity. Of the 31 patients, 14 experienced grade 3 AEs. One patient experienced a grade 4 AE of respiratory disease. The study drug was interrupted due to the event. The event was ongoing at the data cut-off date. Of the 31 patients, one patient discontinued study treatment due to AE of grade 3 stress cardiomyopathy. The patient recovered from the event.

Preliminary clinical results suggest that combination treatment with anti-PD-1 (nivolumab) and anti-LAG3 (relatlimab) agents has the potential for increased benefit compared with anti-PD-1 therapy alone, while having an acceptable safety profile similar to the safety profile of nivolumab monotherapy. In patients with advanced melanoma previously treated with anti-PD-1 /PD-L1 therapy, the objective response rate (ORR) of the combination was 11 .5% (n = 61 ), with a disease control rate of 49% (Ascierto et al., Ann Oncol, 28 (Supplement 5): mdx440.011 , 2017).

Tawbi et al. (A/. Engl. J. Med., 386: 26-34, 2022) reported results from the completed Phase III trial, RELATIVITY-047 (CA224-047; NCT03470922), assessing the efficacy and safety of dual inhibition of LAG3 and PD-1 therapies in combination with relatlimab, a human lgG4 LAG3-blocking antibody, and nivolumab, a PD-1 -blocking antibody, compared with standard-care nivolumab alone. The study enrolled 714 previously untreated patients with histologically confirmed, unresectable Stage III or IV melanoma. Patients were stratified according to LAG3 expression, PD-L1 expression, BRAF mutation status, and metastatic stage. The primary efficacy endpoint was progression-free survival (PFS), as determined by blinded independent central (BICR) review per Response Evaluation Criteria in Solid Tumors, Version 1 .1 (RECIST v1 .1 ). Secondary endpoints included overall survival (OS) and ORR (Tawbi et al., N. Engl. J. Med., 386: 26-34, 2022).

Blinded independent assessment of PFS was longer with relatlimab plus nivolumab than with nivolumab. Patients treated with relatlimab plus nivolumab had twice the median PFS and a 25% lower risk of disease progression or death than nivolumab alone (hazard ratio [HR]: 0.75; p = 0.006 by the logrank test). A 12% difference in landmark PFS between the groups was observed at 12 months. The longer PFS with relatlimab plus nivolumab than with single-agent nivolumab was associated with a slightly greater incidence of adverse events and a health-related quality of life (HRQoL) measures similar to that observed with nivolumab. Combination treatment with relatlimab and nivolumab also showed a PFS benefit over nivolumab in prespecified subgroups. Patients with characteristics that are typically associated with a worse prognosis, such as visceral metastases, high tumor burden, elevated levels of serum lactate dehydrogenase, or mucosal or acral melanoma, had improved outcomes. Expression of LAG3 or PD-L1 was not predictive of PFS benefit with combination treatment with relatlimab plus nivolumab over nivolumab. However, a benefit of combination treatment with relatlimab and nivolumab over nivolumab was observed across BRAF-mutant and wild-type subgroups (Tawbi et al., N. Engl. J. Med., 386: 26-34, 2022).

Confirmed ORR by BICR was numerically increased from 32.6% (95% confidence interval [Cl]: 27.8 to 37.7) with nivolumab alone to 43.1% (95% Cl: 37.9 to 48.4) in the relatlimab plus nivolumab treatment group. Moreover, a non-statistically significant improvement in OS was also observed with relatlimab plus nivolumab over nivolumab alone corresponding to an HR of 0.80 (95% Cl: 27.8 to 37.7). Median OS was not reached (95% Cl: 34.2 to not reached) compared with 34.1 months (95% Cl: 25.2 to not reached), respectively.

A total of 470 patients (65.8%) discontinued treatment (237 patients (66.8%) in the relatlimab plus nivolumab group and 233 patients (64.9%) in the nivolumab group), with most discontinuations attributed to disease progression (reported in 36.3% and 46.0% of patients, respectively) (Tawbi et al., N. Engl. J. Med., 386: 26-34, 2022).

Infusion-related adverse reactions occurred in 5.9% of patients who received combination treatment with relatlimab and nivolumab compared with 3.6% of patients who received nivolumab. Grade 3 or 4 treatment-related adverse events occurred in 18.9% of patients in the relatlimab plus nivolumab group and in 9.7% in the nivolumab group. The most common Grade 3 or 4 treatment-related adverse events in the relatlimab plus nivolumab group included increased levels of lipase (in 1 .7% of the patients), ALT (1 .4%), and AST (1 .4%), as well as fatigue (1 .1 %). Treatment-related adverse events (of any grade) leading to discontinuation were experienced by 14.6% of patients in the relatlimab plus nivolumab group compared with 6.7% of those in the nivolumab group. In all, five treatment-related deaths were reported and considered by investigators to be related to treatment: three deaths in patients in the relatlimab plus nivolumab group (0.8%) (hemophagocytic lymphohistiocytosis, acute pulmonary edema, and pneumonitis) and two deaths in the nivolumab group (0.6%) (sepsis and myocarditis in 1 patient and pneumonia in 1 patient). The most common categories of immune-related adverse events reported in the relatlimab plus nivolumab group were hypothyroidism or thyroiditis (in 18.0% of the patients), rash (9.3%), and diarrhea or colitis (6.8%) (Tawbi et al., N. Engl. J. Med., 386: 26-34, 2022).

Given that the mechanisms for optimal targeting of immune regulation in the tumor environment are still under exploration, rational new approaches to increase response rates to first-line CPI therapy are warranted.

B. Study Phases

The study consists of three phases: screening, treatment, and follow-up.

Screening Phase

Patients are evaluated for study eligibility during a 28-day screening period (Days -28 to -1 ). Patients who are determined to be eligible on the basis of screening assessments are randomized to study treatment.

Patients whose tumors have a known epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) genetic aberrations are excluded from the study. Patients with tumors of non-squamous histology with unknown EGFR or ALK mutational status are required to be tested prior to enrollment. Patients with tumors of squamous histology who have an unknown EGFR or ALK mutational status are not required to be tested at pre-screening/screening.

Treatment Phase

Approximately 180 participants are randomly assigned to each treatment arm in a 1 :1 ratio, enrolling approximately 90 participants per arm. Randomization uses a permuted-block randomization method to ensure a balanced assignment to each treatment arm and will be stratified according to the following criteria:

• PD-L1 expression (tumor proportion score (TPS) or tumor cells (TCs) < 1 % vs. 1 %— 49% vs. > 50% by health authority approved local assay).

• Histology (SQ NSCLC vs. NSQ NSCLC).

• Smoking history (Current/Former vs Never).

To enable an adequate representation of all PD-L1 expression subgroups (participants with TPS or TCs < 1 %, 1 %-49%, and > 50%) and reflect the natural distribution of PD-L1 expression observed among patients with NSCLC in the first-line treatment setting, the proportion of participants enrolled in the TPS/TCs < 1 % and TPS/TCs 1 %-49% PD-L1 expression subgroups is capped at approximately 40% of the total planned enrollment (72 participants), as assessed by a local health authority-approved PD-L1 immunohistochemistry (IHC) assay.

Safety Run-In Evaluation

An initial safety run in evaluation is implemented to assess the safety and tolerability of the novel combination of blinded RO7247669 and chemotherapy. During the safety run-in evaluation, a minimum of 12 participants with NSCLC of each histology (SQ and NSQ) are required. This comprises a minimum of 6 participants per histology per arm, corresponding to a total of approximately 24 participants. These participants are evaluated for safety after they have had the opportunity to complete two cycles of treatment (which is estimated as approximately 6 months after the first participant has been randomized). Participants from each 12-patient group who withdraw from treatment before completing two cycles of treatment are also included in the safety run-in evaluation. After enrollment of the first 12 patients per histology group, randomization continues, but is temporarily suspended if a cap of 22 participants per NSCLC histology (approximately 1 1 participants in Arm A and 1 1 in Arm B) is reached before the safety run-in is cleared.

Assessments

Tumor assessments are performed at baseline and every 6 weeks (± 7 days) for 48 weeks following Day 1 , Cycle 1 , regardless of treatment dose delays. After completion of the Week 48 tumor assessment, tumor assessments are required every 9 weeks (± 7 days) thereafter, regardless of dose delays, until radiographic disease progression per Response Criteria in Solid Tumors, Version 1 .1 (RECIST v1 .1 ), withdrawal of consent, study termination, or death, whichever occurs first. Participants who are treated beyond disease progression per RECIST v1 .1 undergo tumor assessments every 6 weeks (± 2 weeks) after initial documentation of progression, or more frequently if clinically indicated, regardless of time in the study, until treatment is discontinued.

Participants who discontinue treatment for reasons other than radiographic disease progression per RECIST v1 .1 (e.g., toxicity, symptomatic deterioration) continue scheduled tumor assessments at the same frequency as would have been followed if the participant had continued study treatment (i.e. , every 6 weeks (± 7 days) for 48 weeks following Cycle 1 , Day 1 , and then every 9 weeks (± 7 days)) thereafter, until radiographic disease progression per RECIST v1 .1 , withdrawal of consent, study termination, or death, whichever occurs first), regardless of whether the patient starts a new anti-cancer therapy.

Participants randomized into the study are asked to complete patient-reported outcome (PRO) questionnaires. Item Libraries (ILs) 85, 132, 188, and 17 from the European Organisation for Research and Treatment of Cancer (EORTC) assess symptoms of lung cancer (i.e., fatigue, cough, chest pain, bone pain, and dyspnea), physical and role functioning, and global HRQoL. Selected items from the National Cancer Institute (NCI) Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE) and the EORTC IL46 focus on presence, frequency of occurrence, severity, and/or degree of interference with daily function and bother of symptomatic treatment toxicities related to treatment with RO7247669, pembrolizumab, and chemotherapy.

Treatment Beyond Progression

During the study, participants who meet the criteria for disease progression as assessed by the investigator according to RECIST v1 .1 and show evidence of clinical benefit may continue treatment with RO7247669 and pembrolizumab at the investigator’s discretion, provided that participants meet all of the following criteria:

• Evidence of clinical benefit.

• Absence of symptoms and signs (including worsening of laboratory values (e.g., new or worsening hypercalcemia)) indicating unequivocal progression of disease.

• Absence of decline in Eastern Cooperative Oncology Group (ECOG) Performance Status that can be attributed to disease progression.

• Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal disease) that cannot be managed by protocol-allowed medical interventions.

Investigator assessment of overall tumor response at all timepoints is based only on RECIST v1 .1 .

Follow-Up Phase

All participants who discontinue study treatment are followed for survival until death, loss to follow-up, participant withdrawal, or study termination.

Example 2: Study Population

Approximately 180 previously untreated participants with locally advanced, unresectable metastatic NSCLC of SQ or NSQ histology who are not eligible for curative surgery or definitive chemoradiotherapy, with no EGFR mutations or ALK genetic aberrations, are enrolled in the CO44194 study. A. Inclusion Criteria

Potential participants are eligible to be included in the study only if all of the following criteria apply:

• Age > 18 years.

• ECOG Performance Status of 0 or 1 .

• Histologically or cytologically documented locally advanced, unresectable (Stage IIIB/IIIC) or metastatic (Stage IV) NSCLC who are not eligible for curative surgery and/or definitive chemoradiotherapy

(8th edition of the UICC/AJCC-staging system). o Patients with NSCLC of mixed histology and patients with small-cell lung cancer are not eligible for enrollment in the study.

• No prior systemic treatment for metastatic NSCLC. o Patients who have received prior neo-adjuvant, adjuvant chemotherapy, radiotherapy, or chemoradiotherapy with curative intent for non-metastatic disease must have experienced a treatment- free interval of at least 12 months from randomization since the last dose of chemotherapy and/or radiotherapy.

• Known tumor PD-L1 status through a documented local assessment using a health authority-approved PD-L1 IHC assay.

• Measurable disease, as defined by RECIST v1 .1 . o Previously irradiated lesions can only be considered measurable disease if disease progression has been unequivocally documented at that site since radiation and the previously irradiated lesion is not the only site of measurable disease.

• Life expectancy > 12 weeks.

• Adequate hematologic and end-organ function, as defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment (Day 1 of Cycle 1 ): o Absolute neutrophil count (ANC) > 1.5 x 10⁹/L (>1500/pL) without granulocyte colonystimulating factor support with the following exception: Patients with benign ethnic neutropenia (BEN) and ANC > 1 .3 x 10⁹/L (> 1300/pL) are eligible. o Lymphocyte count > 0.5 x 10⁹/L (> 500/pL). o Platelet count > 100 x 10⁹/L (> 100,000/pL) without transfusion. o Hemoglobin > 90 g/L (> 9 g/dL). Patients may be transfused or receive erythropoietic treatment as per local standard of care to meet this criterion. o Aspartate aminotransferase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP) < 2.5 x upper limit of normal (ULN), with the following exceptions: patients with documented liver metastases: AST and ALT < 5 x ULN; patients with documented liver or bone metastases: ALP < 5 x ULN. o Total bilirubin < 1 .5 x ULN with the following exception: patients with known Gilbert disease: bilirubin level < 3 x ULN. o Creatinine clearance (CrCI) > 45 mL/min, calculated with use of the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of CrCI. o Albumin > 25 g/L (> 2.5 g/dL). o For patients not receiving therapeutic anticoagulation: International Normalized Ratio (INR) and activated partial thromboplastin time (aPTT) < 1 .5 x ULN. For patients receiving therapeutic anticoagulation: stable anticoagulant regimen.

• Negative HIV test at screening. Individuals with a positive HIV test at screening are eligible, provided they are stable on anti-retroviral therapy, have a CD4 count > 200/pL, and have an undetectable viral load.

• Negative hepatitis B surface antigen test at screening.

• Positive hepatitis B surface antibody (HBsAb) test at screening, or negative HBsAb at screening accompanied by either negative total hepatitis B core antibody (HBcAb) or positive total HBcAb test followed by a negative (per local laboratory definition) hepatitis B virus (HBV) DNA test.

• Negative hepatitis C virus (HCV) antibody test at screening or positive HCV antibody test followed by a negative HCV RNA test at screening.

• Adequate cardiovascular function, as evidenced by the following: o New York Heart Association (NYHA) Heart Failure Class II or less. o Baseline-corrected QT (through use of Fridericia's formula (QTcF)) interval < 480 ms. If the QTcF interval is longer than 480 ms but is shorter than 500 ms, the patient may undergo a cardiac evaluation and will be considered for treatment in case of no clinically significant findings. o Resting systolic blood pressure < 150 mmHg and diastolic blood pressure 100 mmHg (average of three or more readings during two or more sessions with a short break between sessions) or no clinically significant hypertension. o Resting heart rate between 45 and 100 bpm (or no clinically significant tachycardia). o Left ventricular ejection fraction (LVEF) > 50%, as assessed by either transthoracic echocardiogram (TTE) or multiple-gated acquisition (MUGA) scan (TTE preferred test) within 6 months prior to initiation of study treatment.

• For female participants of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating eggs.

• For male participants: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating sperm.

B. Exclusion Criteria

Potential participants are excluded from the study if any of the following criteria apply:

• NSCLC known to have a mutation in the EGFR gene or an ALK fusion oncogene. o Patients with tumors of non-squamous histology with unknown EGFR or ALK mutational status are required to be tested (by local or central testing with a validated health authority approved test or CE- marked test in the EU) prior to enrollment. Patients with tumors of squamous histology who have an unknown EGFR or ALK mutational status are not required to be tested at pre-screening/screening.

• Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases. Asymptomatic patients with treated CNS lesions are eligible, provided that all of the following criteria are met:

• Measurable disease, per RECIST v1 .1 , must be present outside the CNS. • The patient has no history of intracranial hemorrhage or spinal cord hemorrhage.

• The patient has not undergone stereotactic radiotherapy within 7 days prior to randomization, whole-brain radiotherapy within 14 days prior to randomization, or neurosurgical resection within 28 days prior to randomization.

• The patient has no ongoing requirement for corticosteroids as therapy for CNS disease.

• If the patient is receiving anti-convulsant therapy, the dose is considered stable.

• Metastases are limited to the cerebellum or the supratentorial region (i.e. , no metastases to the midbrain, pons, medulla, or spinal cord).

• There is no evidence of interim progression between completion of CNS-directed therapy and initiation of study treatment.

• There is no evidence of significant vasogenic edema.

Asymptomatic patients with CNS metastases newly detected at screening are eligible for the study after receiving radiotherapy or surgery, with no need to repeat the screening brain scan.

• Spinal cord compression not definitively treated with surgery and/or radiation or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for > 2 weeks prior to initiation of study treatment.

• History of leptomeningeal disease.

• Uncontrolled tumor-related pain.

• Patients requiring pain medication must be on a stable regimen at study entry. o Symptomatic lesions amenable to palliative radiotherapy (e.g., bone metastases or metastases causing nerve impingement) should be treated prior to initiation of study treatment. Patients should be recovered from the effects of radiation. There is no required minimum recovery period. o Asymptomatic metastatic lesions that would likely cause functional deficits or intractable pain with further growth (e.g., epidural metastasis that is not currently associated with spinal cord compression) should be considered for locoregional therapy, if appropriate, prior to enrollment.

• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once a month or more frequently). Patients with indwelling catheters (e.g., PLEURX®) are allowed.

• Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1 .5 mmol/L, calcium > 12 mg/dL, or corrected calcium greater than ULN).

• Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren syndrome, Guillain-Barre syndrome, or multiple sclerosis, with the following exceptions: o Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study. o Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study. o Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met: Rash must cover < 10% of body surface area; Disease is well controlled at baseline and requires only low-potency topical corticosteroids; no occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months.

• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug- induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on the screening chest computed tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

• Active tuberculosis (TB), as documented by a positive purified protein derivative (PPD) skin test or TB blood test and confirmed by a positive chest X-ray within 3 months prior to initiation of study treatment. Patients with a positive PPD skin test or TB blood test followed by a negative chest X-ray may be eligible for the study.

• Untreated latent TB.

• Current treatment with anti-viral therapy for HBV or HCV.

• Significant cardiovascular disease within 3 months prior to randomization, including any of the following: hypertensive crisis or encephalopathy, unstable angina, transient ischemic attack or stroke, congestive heart failure (according to the New York Heart Association classification), serious cardiac arrhythmia requiring treatment (exceptions are atrial fibrillation, paroxysmal supraventricular tachycardia), history of thromboembolic events (such as myocardial infarction, stroke, or pulmonary embolism), troponin T (TnT) or troponin I (Tnl) greater than or equal to the institutional ULN. Patients with TnT or Tnl levels between > 1 and < 2 x ULN are permitted to enroll in the study if repeat levels are < 1 x ULN. If repeat levels are between > 1 and < 2 x ULN, the patient may undergo a cardiac evaluation and will be considered for treatment in case of no clinically significant findings.

• Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study.

• History of malignancy other than NSCLC within 5 years prior to randomization, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate > 90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal breast carcinoma in situ, or Stage I uterine cancer.

• Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia, or any active infection that could affect patient safety.

• Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study.

• Prior allogeneic stem cell or solid organ transplantation.

• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications. • Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during study treatment or within 5 months after the final dose of study treatment.

• Treatment with investigational therapy within 28 days prior to initiation of study treatment.

• Any anti-cancer therapy, including hormonal therapy, within 21 days prior to initiation of study treatment.

• Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including, but not limited to, anti-cytotoxic T lymphocyte-associated protein 4 (CTLA4), anti-T cell immunoreceptor with Ig and tyrosine-based inhibition motif domains (TIGIT), anti-PD-1 and anti-PD-L1 therapeutic antibodies, and anti-LAG3) agents.

• Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin-2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment.

• Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor (TNF) agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions: o Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study. o Patients who received mineralocorticoids (e.g., fludrocortisone), inhaled or low-dose corticosteroids for chronic obstructive pulmonary disease or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study.

• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies, fusion proteins, or platinum-containing compounds.

• Known hypersensitivity to Chinese hamster ovary cell products or to any component of the RO7247669 or pembrolizumab formulation.

• Known allergy or hypersensitivity or other contraindication to any component of the chemotherapy regimen the patient may receive during the study.

• Pregnancy or breastfeeding, or intention of becoming pregnant during the study, within 4 months after the final dose of RO7247669 and pembrolizumab, or 6 months after the final dose of paclitaxel, pemetrexed or carboplatin.

• Known targetable c-ROS oncogene 1 (R0S1), BRAF^VB00E or rearranged during transfection (RET) proto-oncogene genomic aberrations. Patients with known targetable R0S1, BRAF^VB00E or RET genomic aberrations are permitted for trial enrollment only if they are ineligible to receive available targeted therapy.

Example 3: Study Treatment and Concomitant Therapy

A. Study Treatment

Error! Reference source not found, provides a description of assigned study treatments for the CO44194 study. Table 6. Study Treatment Description

AUC = area under the concentration-time curve; Q3W = every 3 weeks.

In this protocol, "study treatment" refers to the following combination of treatments assigned to participants in Arm A or Arm B as part of this study:

Arm A:

• For patients with non-squamous (NSQ) NSCLC, induction treatment with blinded RO7247669 in combination with pemetrexed and carboplatin every three weeks (Q3W) for four cycles, followed by Q3W maintenance therapy with blinded RO7247669 in combination with pemetrexed Q3W

• For patients with squamous (SQ) NSCLC, blinded RO7247669 in combination with paclitaxel and carboplatin Q3W for four cycles, followed by blinded treatment with RO7247669 Q3W.

Arm B:

• For patients with NSQ NSCLC, induction treatment with blinded pembrolizumab in combination with pemetrexed and carboplatin Q3W for four cycles, followed by maintenance therapy with blinded pembrolizumab in combination with pemetrexed Q3W .

• For patients with SQ NSCLC, blinded treatment with pembrolizumab in combination with paclitaxel and carboplatin Q3W for four cycles, followed by blinded pembrolizumab Q3W.

Blinded RO7247669 and Blinded Pembrolizumab

Participants receive blinded RO7247669 (600 mg Q3W) or blinded pembrolizumab (200 mg Q3W) by IV infusion. Administration of study treatment is performed in a monitored setting where there is immediate access to trained personnel and adequate equipment and medicine to manage potentially serious reactions. The 600-mg dose of RO7247669 Q3W and the 200-mg dose of pembrolizumab Q3W remain the same throughout the study.

Participants who experience an infusion-associated adverse event may be premedicated with an antihistamine and/or antipyretic medication for subsequent doses and beyond at the discretion of the investigator, but the infusion time may not be decreased for that infusion. RO7247669 and pembrolizumab infusions are administered to participants per the instructions outlined in Error! Reference source not found..

Table 7. Administration of First and Subsequent Infusions of RO7247669 or Pembrolizumab

Paclitaxel

Paclitaxel 200 mg/m² is administered as an IV infusion to participants over 3 hours Q3W for four cycles as per local practice and labels. All participants should be premedicated with oral or an IV steroid and antihistamines according to the approved product label and/or standard practice. Additional premedications should be administered as per standard practice. Paclitaxel should be completely administered before initiating carboplatin dose.

Pemetrexed

All participants receive the appropriate supplementation with vitamin B12 and folic acid and corticosteroid prophylaxis as listed below (or as per local label): • Folic acid 350-1000 ng orally (PO): Participants must take at least five doses of folic acid during the 7 days preceding the first dose of pemetrexed, and folic acid dosing must continue during the full course of therapy and for 21 days after the final dose of pemetrexed.

• Anti-emetic prophylaxis with dexamethasone 4 mg (or equivalent) PO twice per day: Participants take dexamethasone the day before, the day of, and the day after pemetrexed administration. Higher or additional doses are permitted for anti-emetic prophylaxis during Cycles 1-4 are but not to exceed doses per the Multinational Association of Supportive Care (MASCC) and ESMO guidelines (Roila et al., Ann Oncol, 27: v119-133, 2016).

Carboplatin

Carboplatin AUC 5 mg/mL • min: Participants receive carboplatin as an IV infusion over 30-60 minutes Q3W for four cycles immediately after paclitaxel or pemetrexed as per local practice and labels. The dose of carboplatin should be calculated using the Calvert formula (see below) and should not exceed 750 mg.

Calvert Formula:

Total dose (in milligrams (mg)) = (target AUC) x (CrCI + 25).

The estimated glomerular filtration rate (GFR) used in the Calvert formula should not exceed 125 mL/min.

Maximum carboplatin dose (mg) = target AUC 5 (mg/mL • min) x (125 + 25) = 5 x 150 mL/min = 750 mg.

Paclitaxel, pemetrexed, and carboplatin are administered to participants as outlined in Error!

Reference source not found..

Table 8. Treatment Regimen for Pemetrexed, Paclitaxel, and Carboplatin

B. Concomitant Therapy

Permitted Therapy

Use of the following concomitant therapies is permitted as described below: • Oral contraceptives. • Hormone-replacement therapy.

• Palliative radiotherapy (e.g., treatment of known bony metastases or symptomatic relief of pain) as outlined below: o In participants without documentation of radiographic disease progression, it is strongly encouraged to maximize supportive care for symptomatic management and to avoid radiotherapy that will interfere with the assessment of tumor target lesions. Treatment with RO7247669 and pembrolizumab may be continued during palliative radiotherapy.

• Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable dose or low-molecular- weight heparin).

• Vaccinations (such as influenza, COVID-19). Live, attenuated vaccines are not permitted.

• Megestrol acetate administered as an appetite stimulant.

• Mineralocorticoids (e.g., fludrocortisone).

• Inhaled or low-dose corticosteroids administered for chronic obstructive pulmonary disease or asthma.

• Low-dose mineralocorticoids administered for orthostatic hypotension or low-dose mineralocorticoids and corticosteroids for adrenocortical insufficiency.

Premedication for pemetrexed, paclitaxel, and carboplatin is permitted. Premedication with antihistamines, antipyretic medications, and/or analgesics may be administered for the second and subsequent RO7247669 and pembrolizumab infusion only, at the discretion of the investigator.

In general, investigators should manage a participant’s care with supportive therapies other than those defined as cautionary or prohibited therapies as clinically indicated, per local standard practice. Participants who experience infusion-associated symptoms may be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine, cimetidine), or equivalent medications per local standard practice. Serious infusion associated-events manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen and p2-adrenergic agonists).

Participants must abstain from taking prescription and non-prescription drugs (including vitamins and dietary or herbal supplements) within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 drug-elimination half-lives (whichever is longer) before the start of study treatment until completion of the follow-up visit, unless, in the opinion of the investigator, the medication will not interfere with the study.

Cautionary Therapy

Systemic corticosteroids, immunosuppressive medications, and TNF inhibitors may attenuate potential beneficial immunologic effects of treatment with RO7247669 and/or pembrolizumab. Therefore, in situations in which systemic corticosteroids, immunosuppressive medications, or TNF inhibitors would be routinely administered, alternatives, including antihistamines, should be considered. If the alternatives are not feasible, systemic corticosteroids, immunosuppressive medications, and TNF inhibitors may be administered at the discretion of the investigator. Systemic corticosteroids or immunosuppressive medications are recommended, at the discretion of the investigator, for the treatment of specific adverse events when associated with RO7247669 and pembrolizumab therapy.

Concomitant use of herbal therapies is not recommended because their pharmacokinetics, safety profiles, and potential drug-drug interactions are generally unknown. However, herbal therapies not intended for the treatment of cancer may be used during the study at the discretion of the investigator.

Prohibited Therapy

Use of the following concomitant therapies is prohibited as described below:

• Investigational therapy (other than protocol-mandated study treatment) within 28 days prior to initiation of study treatment and during study treatment.

• Concomitant therapy intended for the treatment of cancer (including, but not limited to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal therapy), whether health authority approved or experimental, for various time periods prior to starting study treatment, depending on the agent, and during study treatment, until disease progression is documented and the participant has discontinued study treatment, with the exception of palliative radiotherapy, radiotherapy to the brain, and local therapy under certain circumstances.

• Live, attenuated vaccines within 4 weeks prior to initiation of study treatment, during study treatment, and for 5 months after the final dose of study treatment.

• Systemic immunomodulatory agents (including, but not limited to, interferons and interleukin-2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment and during study treatment because these agents could potentially increase the risk for autoimmune conditions when given in combination with study treatment.

Example 4: Efficacy and Safety Assessments

A. Efficacy Assessments

Tumor Evaluation

Participants in the CO44194 study undergo tumor assessments at screening, every 6 weeks (± 7 days) for the first 48 weeks following treatment initiation (Day 1 of Cycle 1 ), and every 9 weeks (± 7 days) thereafter, regardless of dose delays. Participants continue to undergo tumor assessments until radiographic disease progression per RECIST v1 .1 or loss of clinical benefit (for participants who continue treatment after radiographic treatment progression), as determined by the investigator, withdrawal of consent, death, or study termination, whichever occurs first.

Participants who are treated beyond disease progression per investigator-assessed RECIST v1 .1 undergo tumor assessments every 6 weeks (± 2 weeks) after initial documentation of progression, or more frequently if clinically indicated, regardless of time in the study until treatment is discontinued. At the investigator's discretion, tumor assessments may be repeated at any time if progressive disease is suspected. Participants who discontinue study treatment (for any reason, including, but not limited to, clinical decline or toxicity) in the absence of radiographic disease progression per investigator-assessed RECIST v1 .1 continue to undergo tumor response assessments at the same frequency until radiographic disease progression per RECIST v1 .1 , withdrawal of consent, death, or study termination, whichever occurs first. In the absence of radiographic disease progression per RECIST v1 .1 , tumor assessments continue regardless of whether a participant starts a new anti-cancer therapy.

All measurable and/or evaluable lesions are assessed and documented at screening. Tumor assessments performed as standard of care prior to obtaining informed consent and within 28 days prior to initiation of study treatment do not have to be repeated at screening, so long as they meet criteria outlined herein.

Response Evaluation

Objective response is determined by the investigator at specified timepoints according to RECIST v1 .1 . Assessments are performed by the same individual, if possible, to ensure internal consistency across visits.

Other endpoints (e.g., PFS, OS, DOR) are calculated programmatically on the basis of investigator assessments of response at each specified timepoint.

Clinical Outcome Assessments

PRO questionnaires are completed to assess the treatment benefit of RO7247669 plus platinumbased chemotherapy. In addition, PRO questionnaires enable the capture of each participant's direct experience with RO7247669 plus platinum-based chemotherapy. PRO data is collected through use of the following questionnaires: EORTC IL85, IL132, IL188, and IL17.

The IL85 is composed of five lung cancer-specific items from the EORTC, assessing cough, shortness of breath, and chest pain. The IL85 takes approximately 3 minutes to complete.

The IL132 consists of three items of relevance to patients with cancer from the EORTC, assessing fatigue. The IL132 takes approximately 2 minutes to complete.

The IL188 is a single item from the EORTC, evaluating bone pain in patients with cancer. The IL188 takes approximately 1 minute to complete.

The IL17 is composed of nine items of relevance to patients with cancer from the EORTC, assessing physical functioning, role functioning, and GHS/QoL. The IL17 takes approximately 4 minutes to complete.

The recall period for these IL assessments is specified to be during the past week.

B. Safety Assessments

Patient-reported outcome (PRO) questionnaires are completed to assess the treatment effects of RO7247669 plus platinum-based chemotherapy versus pembrolizumab plus platinum-based chemotherapy. In addition, PRO questionnaires enable the capture of each participant's direct experience with RO7247669 in combination with platinum-based chemotherapy.

PRO data are collected through use of the following questionnaires: selected items from the NCI PRO-CTCAE and the EORTC IL46.

The NCI PRO-CTCAE is a validated item bank that is used to characterize the presence, frequency of occurrence, severity, and/or degree of interference with daily function of 78 patient- reportable symptomatic treatment toxicities (Basch et al., J Natl Cancer Inst, 106: 1 -1 1 , 2014; Dueck et al., JAMA Oncol, 1 : 1051 -1059, 2015). The NCI PRO-CTCAE comprises 124 questions that are rated either dichotomously (for determination of presence vs. absence) or on a 5-point Likert scale (for determination of frequency of occurrence, severity, and interference with daily function). Treatment toxicities can occur with observable signs (e.g., vomiting) or non-observable symptoms (e.g., nausea). The standard NCI PRO-CTCAE recall period is the previous 7 days.

A subset of eight signs and symptoms deemed most applicable to the current study treatments have been selected for this study. The signs and symptoms have been selected on the basis of the known side effects of the marketed drugs included in the standard of care, namely pembrolizumab and platinum-based chemotherapy.

The EORTC IL46 is a validated single-item questionnaire assessing the overall impact of side effects. The standard EORTC IL46 recall period is during the previous week.

Example 5: Statistical Considerations

Statistical Hypotheses

The purpose of this study is hypothesis generation regarding the effect of RO7247669 in combination with platinum-based chemotherapy (Arm A) compared with pembrolizumab plus platinumbased chemotherapy (Arm B) on the basis of the primary endpoints, investigator-assessed objective response rate (ORR) and progression-free survival (PFS). No formal statistical hypotheses are tested for this study.

Sample Size Determination

A total sample size of approximately 180 patients is planned for this study.

With this sample size, a 20% improvement in ORR (i.e. , AORR) in Arm A relative to Arm B (assuming a 48% ORR in Arm B) will have a 95% Cl of 3.7% to 34.9%. The primary analysis of ORR is conducted approximately 3 months after the last patient is randomized.

The primary analysis of PFS is conducted when approximately 136 total PFS events have been observed. This is projected to occur approximately 37 months after the first patient has been randomized. A target PFS HR of 0.7 will have a 95% confidence interval (Cl) of 0.50 to 0.98 assuming exponentially distributed event times. Error! Reference source not found, and 10 show the Cis for several possible true underlying improvements in ORR and PFS in favor of Arm A.

Table 9. Confidence Intervals for Several Possible True Underlying AORR Values

a Calculated using Newcombe method.

Table 10. Confidence Intervals for Several Possible True Underlying PFS HR Values

Analysis Sets

The participant analysis sets for the purposes of analyses are defined in Error! Reference source not found..

Table 11. Participant Analysis Sets

Statistical Analyses

All efficacy analyses are performed on the full analysis set, unless otherwise specified. The analysis of ORR is performed for participants in all randomized participants with measurable disease at baseline, as determined by the investigator according to RECIST v1 .1 . No formal hypothesis testing is conducted; any treatment arm comparison and their associated p-value is generated for descriptive purpose only.

All safety analyses are performed on the safety-evaluable population, unless otherwise specified.

The primary efficacy endpoints are confirmed ORR and PFS, as assessed by the investigator according to RECIST v1 .1 .

The analysis population for ORR is all randomized patients with measurable disease at baseline. The primary analysis of the primary endpoint of investigator-assessed ORR occurs once all randomized patients have been treated and followed until their post-baseline tumor assessment 12 weeks or 3 months after last patient has been randomized, whichever occurs first.

Investigator-assessed PFS is analyzed in all patients randomized. An interim analysis of the investigator-assessed PFS is conducted at the time of the primary analysis of ORR. The primary analysis of the primary endpoint of investigator-assessed PFS occurs after approximately 136 events have been observed.

ORR is defined as the percentage of participants who experience a complete response or partial response on two consecutive occasions > 4 weeks apart, as determined by the investigator according to RECIST v1 .1 . Participants without post-baseline overall response assessments are counted as nonresponders.

An estimate of the difference between the ORR in the two arms is computed along with its 95% confidence interval (Cl) using the Newcombe method. The 95% Cl of the confirmed ORR is calculated for each treatment arm using the Wilson score method. The Cochran-Mantel-Haenszel test is used to compare the ORR between the two treatment arms, stratified according to the protocol-defined stratification factors.

PFS is defined as the time from randomization to the date of first documented disease progression or death, whichever occurs first. Disease progression for PFS analysis is determined on the basis of investigator assessment using RECIST v1 .1 . Data from participants who have not experienced disease progression or who have not died at the time of analysis are censored at the time of the last tumor assessment. Data from participants with no post-baseline tumor assessment are censored at the date of randomization.

A stratified Cox-proportional hazards model is used to estimate the HR and its 95% Cl. The two- sided stratified log-rank test is used to compare PFS between the two treatment arms. Kaplan-Meier methodology is used to estimate the PFS curve and median PFS for each treatment arm. The Brookmeyer Crowley methodology is used to construct the 95% Cl for the median PFS for each treatment arm.

Example 6: A Phase II, Multicenter, Randomized, Double-Blind Study of RO7247669 Combined With Nab-Paclitaxel Compared With Pembrolizumab Combined With Nab-Paclitaxel In Participants With Previously Untreated, PD-L1 -Positive, Locally- Advanced Unresectable Or Metastatic Triple-Negative Breast Cancer

A. Overview of Study Design

CO44194 is a Phase II, randomized, double-blind, global, multicenter study designed to evaluate the efficacy, safety, and pharmacokinetics of RO7247669 in combination with nab-paclitaxel compared with pembrolizumab plus nab-paclitaxel in patients with previously untreated, locally advanced, unresectable or metastatic (Stage IV) PD-L1 -positive triple-negative breast cancer (TNBC). The design of the study is shown in Figs. 2 and 3A-3C.

Participants are selected on the basis of a positive PD-L1 expression on tumor as assessed through central testing, defined as meeting at least one of the following thresholds specific to each assay: the investigational Dako PD-L1 immunohistochemistry (IHC) 22C3 pharmDx assay Combined Positive Score (CPS) > 10 and/or investigational VENTANA PD-L1 (SP263) Assay Tumor Area Positivity score (TAP) > 5% and/or investigational VENTANA PD-L1 (SP142) Assay PD-L1 -expressing tumor-infiltrating immune cells (IC) > 1%. CPS is the number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100. IC is defined as the presence of discernible PD-L1 staining of any intensity in tumor-infiltrating immune cells covering the tumor area occupied by tumor cells, associated intratumoral, and contiguous peritumoral stroma. TAP is defined as the percentage of stained tumor and immune cell within the total tumor area.

The primary population of interest is all randomized participants, hereinafter referred to as full analysis set (FAS). The 22C3-positive analysis set is defined as all randomized participants with CPS > 10 using the investigational Dako PD-L1 IHC 22C3 pharmDx assay. The SP263-positive analysis set is defined as all randomized participants with TAP > 5% using the investigational VENTANA PD-L1 (SP263) Assay. The SP142-positive analysis set is defined as all randomized participants with IC > 1 % using the investigational VENTANA PD-L1 (SP142) Assay. The safety analysis set (SAS) is defined as all participants who are randomized and received at least one dose of any study treatment.

Objectives and corresponding endpoints of the study are provided in Table 12, below. Progression-free survival (PFS) is the primary endpoint.

Table 12. Objective and Endpoints

Several key aspects of the study design and study population are summarized in Table 13, below.

Table 13. Overall Design and Study Population

Study Treatment

Approximately 160 participants are randomized in the study to receive either RO7247669 plus nab-paclitaxel (Arm A) or pembrolizumab plus nab-paclitaxel (Arm B) as follows:

1 . Arm A (n = approximately 80): RO7247669 plus nab-paclitaxel - Participants receive blinded RO7247669, administered every 3 weeks (a “cycle”), plus nab-paclitaxel, administered weekly on a repeating schedule of 3 weeks on followed by 1 week off, until disease progression or treatment discontinuation.

2. Arm B (n = approximately 80): Pembrolizumab plus nab-paclitaxel - Participants receive blinded pembrolizumab, administered every 3 weeks (a “cycle”), plus nab-paclitaxel, administered weekly on a repeating schedule of 3 weeks on followed by 1 week off, until disease progression or treatment discontinuation.

Blinded RO7247669 and Blinded Pembrolizumab

Administration of blinded RO7247669 (600 mg every three weeks (Q3W)) or blinded pembrolizumab (200 mg Q3W) by IV infusion is performed in a monitored setting where there is immediate access to trained personnel and adequate equipment and medicine to manage potentially serious reactions.

The initial dose is delivered over 60 (± 15) minutes. If the 60-minute infusion is tolerated without infusion-associated adverse events (fever or chills), the second infusion may be delivered over 30 (± 10) minutes. If the 30-minute infusion is well tolerated, all subsequent infusions may be delivered over 30 (± 10) minutes.

Participants who experience an infusion-associated adverse event may be premedicated with an antihistamine and/or antipyretic medication for the next infusion, but the infusion time may not be decreased for that infusion.

Nab-Paclitaxel

The starting dose level of nab-paclitaxel in this study is 100 mg/m² administered intravenously over 30 minutes weekly on a repeating schedule of 3 weeks on followed by 1 week off. Doses of nab- paclitaxel should not be administered more frequently than every 7 days.

On days of scheduled infusions of blinded RO7247669 or pembrolizumab and nab-paclitaxel, chemotherapy is administered after infusion of RO7247669 or pembrolizumab. Dose Modification

Modification of the RO7247669 or pembrolizumab dose is not permitted. Dose modifications for nab-paclitaxel may be implemented according to local guidelines and practices.

Duration of Participation

Treatment continues until investigator-assessed disease progression per Response Evaluation Criteria in Solid Tumors v1 .1 . The total duration of study participation for each individual is expected to range from 1 day to more than 30 months.

Benefit-Risk Assessment

The purpose of the study is to assess the efficacy, safety, and pharmacokinetics of RO7247669, a novel immunomodulating therapy, in combination with chemotherapy to address a significant unmet medical need in patients with previously untreated, locally-advanced, unresectable or metastatic PD-L1 - positive TNBC who are not eligible for curative-intent surgery and/or curative-intent chemoradiotherapy.

Patients with advanced or metastatic solid tumors present a great unmet need. Benefit from cancer immunotherapy with CPI monoclonal antibodies, such as those targeting PD-1/ PD-L1 , is predominantly observed in a subset of patients with inflamed tumor phenotypes. However, response is not guaranteed even in this patient subset owing to either primary or acquired resistance mechanisms. Nearly all patients with metastatic TNBC eventually progress and die from the disease, and thus even incremental progress in therapy is critical. Upregulated LAG3 expression on T cells is associated with T- cell dysfunction, potentially resulting in adaptive resistance to anti-PD-1/PD-L1 therapies (Sharma et al., Cell, 168: 707-723, 2017). Therefore, LAG3 blockade of tumor-infiltrating lymphocytes (TILs) may overcome or prevent resistance mechanisms to anti-PD-1/PD-L1 and help restore or increase T-cell proliferation and cytotoxic effector functions.

Indeed, preliminary clinical results suggest that combination treatment with anti-PD-1 (nivolumab) and anti-LAG3 (relatlimab) agents has the potential for increased benefit compared with anti-PD-1 therapy alone, while having an acceptable safety profile similar to the safety profile of nivolumab monotherapy. In patients with advanced melanoma previously treated with anti-PD-1 /PD-L1 therapy, the objective response rate (ORR) of the combination was 11 .5% (n = 61 ), with a disease control rate (DCR) of 49% (Ascierto et al., Ann Oncol, 28(Suppl 5):mdx440.011 , 2017).

Tawbi et al. (N Eng J Med, 386: 26-34, 2022) reported results from the completed Phase III trial, RELATIVITY-047 (CA224-047; NCT03470922), assessing the efficacy and safety of dual inhibition of LAG3 and PD-1 therapies in combination with relatlimab, a human lgG4 LAG3-blocking antibody, and nivolumab, a PD-1 -blocking antibody, compared with standard-care nivolumab alone. The study enrolled 714 previously untreated patients with histologically confirmed, unresectable Stage III or IV melanoma. Patients were stratified according to LAG3 expression, PD-L1 expression, BRAF mutation status, and metastatic stage. The primary efficacy endpoint was PFS, as determined by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1 .1 ). Secondary endpoints included OS and ORR.

Blinded independent assessment of PFS was longer with relatlimab plus nivolumab than with nivolumab. Patients treated with relatlimab plus nivolumab had twice the median PFS and a 25% lower risk of disease progression or death than nivolumab alone (hazard ratio [HR]: 0.75; p = 0.006 by the logrank test). A 12% difference in landmark PFS between the groups was observed at 12 months. The longer PFS with relatlimab plus nivolumab than with single-agent nivolumab was associated with a slightly greater incidence of adverse events and health-related quality of life (HRQoL) measures similar to that observed with nivolumab. Combination treatment with relatlimab and nivolumab also showed a PFS benefit over nivolumab in prespecified subgroups. Patients with characteristics that are typically associated with a worse prognosis, such as visceral metastases, high tumor burden, elevated levels of serum lactate dehydrogenase, or mucosal or acral melanoma, had improved outcomes. Expression of LAG3 or PD-L1 was not predictive of PFS benefit with combination treatment with relatlimab plus nivolumab over nivolumab. However, a benefit of combination treatment with relatlimab and nivolumab over nivolumab was observed across BRAF-mutant and wild-type subgroups (Tawbi et al., N Eng J Med, 386: 26-34, 2022).

Confirmed ORR by BICR was numerically increased from 32.6% (95% Cl: 27.8 to 37.7) with nivolumab alone to 43.1% (95% Cl: 37.9 to 48.4) in the relatlimab plus nivolumab treatment group. Moreover, a non-statistically significant improvement in OS was also observed with relatlimab plus nivolumab over nivolumab alone corresponding to an HR of 0.80 (95% Cl: 27.8 to 37.7). Median OS was not reached (95% Cl: 34.2 to not reached) compared with 34.1 months (95% Cl: 25.2 to not reached) in the relatlimab plus nivolumab and nivolumab alone groups, respectively.

A total of 470 patients (65.8%) discontinued treatment (237 patients (66.8%) in the relatlimab plus nivolumab group and 233 patients (64.9%) in the nivolumab group), with most discontinuations attributed to disease progression (reported in 36.3% and 46.0% of patients, respectively) (Tawbi et al., N Eng J Med, 386: 26-34, 2022).

Infusion-related adverse reactions occurred in 5.9% of patients who received combination treatment with relatlimab and nivolumab compared with 3.6% of patients who received nivolumab. Grade 3 or 4 treatment-related adverse events occurred in 18.9% of patients in the relatlimab plus nivolumab group and in 9.7% in the nivolumab group. The most common Grade 3 or 4 treatment-related adverse events in the relatlimab plus nivolumab group included increased levels of lipase (reported in 1 .7% of the patients), alanine transaminase (ALT) (1 .4%), and aspartate transaminase (AST) (1 .4%), as well as fatigue (1 .1%). Treatment-related adverse events (of any grade) leading to discontinuation were experienced by 14.6% of patients in the relatlimab plus nivolumab group compared with 6.7% of patients in the nivolumab group. In all, five treatment-related deaths were reported and considered by investigators to be related to treatment: three deaths in patients in the relatlimab plus nivolumab group (0.8%) (hemophagocytic lymphohistiocytosis, acute pulmonary edema, and pneumonitis) and two deaths in the nivolumab group (0.6%) (sepsis and myocarditis in 1 patient and pneumonia in 1 patient). The most common categories of immune-related adverse events reported in the relatlimab plus nivolumab group were hypothyroidism or thyroiditis (in 18.0% of the patients), rash (9.3%), and diarrhea or colitis (6.8%) (Tawbi et al., N Eng J Med, 386: 26-34, 2022). Given that the mechanisms for optimal targeting of immune regulation in the tumor environment are still under exploration, rational new approaches to increase efficacy of first-line CPI therapy, while maintaining reasonable tolerability, are warranted.

B. Study Design and Rationale

• Arm A (n = approximately 80): RO7247669 plus nab-paclitaxel - Participants receive blinded RO7247669, administered every 3 weeks (a “cycle”), plus nab-paclitaxel, administered weekly on a repeating schedule of 3 weeks on followed by 1 week off, until disease progression or treatment discontinuation.

• Arm B (n = approximately 80): Pembrolizumab plus nab-paclitaxel - Participants receive blinded pembrolizumab, administered every 3 weeks (a “cycle”), plus nab-paclitaxel, administered weekly on a repeating schedule of 3 weeks on followed by 1 week off, until disease progression or treatment discontinuation.

The first approximately 12 participants are included in a safety run-in period in which participants are randomized equally to RO7247669 plus nab-paclitaxel or pembrolizumab plus nab-paclitaxel (targeting 6 participants on each combination). The remaining participants continue to be randomized in a 1 :1 ratio to receive RO7247669 plus nab-paclitaxel or pembrolizumab plus nab-paclitaxel.

For each individual participant, the study consists of three phases: screening, treatment, and follow-up.

Screening Phase

After providing informed consent, patients are evaluated for study eligibility during a 28-day screening period (Days -28 to -1 in relation to the first dose of study treatment). Patients who are determined to be eligible on the basis of screening assessments are randomized to study treatment (and thereafter are referred to as “participants”). Patients who do not meet the criteria for participation in this study (screen failure) may qualify for one re-screening opportunity.

Treatment Phase

Approximately 160 participants are randomly assigned to each treatment arm. Randomization uses a permuted-block randomization method to ensure a balanced assignment to each treatment arm and is stratified according to the following criteria: prior cancer immunotherapy exposure (yes vs. no) and initial presentation of TNBC as de-novo metastatic (Stage IV) disease (yes vs. no). No crossover is allowed between arms (i.e. , RO7247669 to pembrolizumab or vice versa).

Safety Run-In Evaluation

An initial safety run-in evaluation is implemented to assess the safety and tolerability of the novel combination of blinded RO7247669 and nab-paclitaxel. The safety run-in evaluation is performed on the safety run-in evaluable analysis set (SRAS), defined as a minimum of 12 randomized participants who received at least one dose of combination treatment (at least 6 participants in each arm). It occurs after participants in the SRAS have had the opportunity to complete 6 weeks of treatment. After randomization of the first approximately 12 participants, screening is paused until the safety run-in is analyzed and cleared.

Assessments

Tumor assessments are performed at baseline and according to the schedule of activities, regardless of treatment dose delays, until radiographic disease progression per RECIST v1 .1 , withdrawal of consent, study termination, or death, whichever occurs first. Participants who undergo palliative therapy to target lesions and are therefore unevaluable for response remain on study and continue tumor assessments until disease progression per RECIST v1 .1 , full withdrawal of consent, loss to follow-up, study termination, or death, whichever occurs first.

Participants who discontinue treatment for reasons other than radiographic disease progression per RECIST v1 .1 (e.g., toxicity, symptomatic deterioration) continue scheduled tumor assessments according to the schedule of activities, until radiographic disease progression per RECIST v1 .1 , withdrawal of consent, loss to follow-up, study termination, or death, whichever occurs first, regardless of whether the patient starts a new anti-cancer therapy.

Safety assessments at study visits include the incidence, nature, and severity of adverse events, protocol-mandated vital signs, laboratory abnormalities, and other protocol-specified tests that are deemed critical to the safety evaluation of the study. The severity of adverse events is assessed according to the NCI Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0). The severity of cytokine release syndrome (CRS) is determined according to the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading Scale.

During the study, samples are collected to monitor RO7247669 concentrations in serum and paclitaxel concentrations in plasma at specified timepoints and to detect the presence of antibodies to RO7247669. Participant samples, including archival and fresh tumor tissue, serum, plasma, and blood samples, are also collected for exploratory biomarker assessments.

Follow-Up Phase

All participants who discontinue study treatment are followed for survival until death, loss to follow-up, participant withdrawal, or study termination. Rationale for Patient Selection Using the Investigational Dako PD-L1 IHC 22C3 pharmDx Assay, Investigational VENTANA PD-L1 (SP142) Assay, and Investigational VENTANA PD-L1 (SP263) Assay

The Dako PD-L1 IHC 22C3 pharmDx Assay, the VENTANA PD-L1 (SP142) Assay, and the VENTANA PD-L1 (SP263) Assay are intended for use as qualitative immunohistochemical assays for the assessment of PD-L1 expression in formalin-fixed, paraffin-embedded (FFPE) TNBC tissue. Results from these devices are used for identification of the PD-L1 -positive patients and to support efficacy analyses.

The KEYNOTE-355 study showed that only patients with mTNBC whose tumors had PD-L1 expression of CPS > 10, as assessed with Dako PD-L1 IHC 22C3 pharmDx assay, derived clinical benefit from pembrolizumab (Cortes et al., Lancet, 396: 1817-1828, 2020). Health authorities, including the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), granted approval of the anti-PD-1 antibody pembrolizumab in combination with chemotherapy for the treatment of patients with advanced TNBC whose tumors are PD-L1 positive, defined as a CPS of > 10 as determined through use of the Dako PD-L1 IHC 22C3 pharmDx assay.

The IMpassion130 study showed that only patients with mTNBC whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells (IC) covering > 1 % of the tumor area), as assessed by the VENTANA PD-L1 (SP142) Assay, derived clinical benefit from atezolizumab in combination with nab-paclitaxel (Schmid et al., NEJM, 379: 2108-2121 , 2018). Health authorities, including the European Medicines Agency (EMA), granted approval of the anti-PD- L1 antibody atezolizumab in combination with nab-paclitaxel for the treatment of patients with advanced TNBC whose tumors are PD-L1 positive, defined as an IC of > 1 % as determined through use of the VENTANA PD-L1 (SP142) Assay.

The diagnostic development for RO7247669 uses the investigational VENTANA (SP142) Assay and the investigational VENTANA (SP263) Assay, the latter having an immunostaining pattern similar that of the Dako PD-L1 IHC 22C3 pharmDx assay (Emens et al., J Natl Cancer Inst, 113: 1005-1016, 2021 ).

The current study randomizes individuals with TNBC whose tumor tissue has a CPS of > 10 or TAP of > 5% or IC of > 1 %, as assessed by a central laboratory with the investigational DAKO PD-L1 IHC 22C3 pharmDx, investigational VENTANA PD-L1 (SP263) Assay and investigational VENTANA PD-L1 (SP142) Assay, respectively. The three assays are expected to have some differences in their detection and prevalence, which are important to understand from this study. For example, the cutoff for SP263 PD-L1 expression is supported by a Roche internal study of PD-L1 expression as determined by the comparison of VENTANA SP263 and DAKO 22C3 assays in 694 primary and metastatic TNBC tissue samples, of which 50% (344 of 694 patients) had a TAP score of > 5%, while the prevalence of 22C3 CPS > 10 was 52% (360 of 694). The prevalence of PD-L1 IC > 1 % using the investigational VENTANA SP142 assay is 41 % based on the IMpassionl 30 study (Schmid et al., NEJM, 379: 2108-2121 , 2018). The inter-assay concordance between samples with a PD-L1 TAP score of > 5% per the SP263 assay and samples with a PD-L1 CPS of > 10 per the 22C3 assay was 77%, while the concordance between PD-L1 TAP score > 5% per the SP263 assay and samples with a PD-L1 IC > 1 % per VENTANA SP142 assay was 73% and the concordance between PD-L1 score of >10% per the 22C3 assay and samples with a PD-L1 IC > 1 % per VENTANA SP142 assay was 74% (Rugo et al., JNCI, 1 13(12): 1733-1743, 2021 ).

Justification for Dose and Schedule

The 600-mg RO7247669 Q3W (600 mg on Day 1 of each 21 -day cycle) dosing regimen was selected on the basis of available clinical PK, efficacy, and safety data from the combined Phase la/lb study NP41300. In Study NP41300, the MTD was not reached, and no DLTs were observed during dose escalation. Greater than 90% occupancy of peripheral PD-1 and LAG3 receptors on CD8⁺ cells was observed at 50 mg of RO7247669 and was sustained at all higher doses. During the dose-escalation part of Study NP41300, responses were observed at 600 mg and 2100 mg. Further modelling of intratumoral PD-1 and LAG3 target engagement using estimated target properties was performed. A dose regimen of 600 mg Q3W was selected to ensure that the majority of participants have at least 90% PD-1 and LAG3 tumor receptor saturation by RO7247669, irrespective of intratumoral spatial heterogeneity and intersubject variability. A dose greater than 600 mg would not be expected to result in further clinical activity.

In Study NP41300, persistent anti-drug antibodies (ADAs) formed in approximately 18% of the total population, and the incidence rate was apparently not dose dependent. An impact on exposure was observed at doses of 50, 150 and 300 mg; therefore, a 600-mg dose is used in the present study to minimize the risk of a loss in exposure due to ADAs.

End of Study and Duration of Participation

A participant is considered to have completed the study if he or she has completed all phases of the study.

Treatment continues until investigator-assessed disease progression per RECIST v1 .1 . The total duration of study participation for each individual is expected to range from 1 day to more than 30 months.

The end of this study is defined as the date of the last visit of the last participant in the study or the date at which the last data point required for statistical analysis or safety follow-up is received from the last participant, whichever occurs later. The end of the study is expected to occur approximately 30 months after the last participant is randomized.

Example 7: Study Population

Approximately 160 patients with metastatic or locally advanced unresectable, PD-L1 -positive, TNBC who have not received prior systemic therapy for the same condition are randomized in the CO44194 study. Locally advanced disease must not be amenable to resection with curative intent, per assessment of the treating investigator/physician. Participants may have received prior chemotherapy and/or cancer immunotherapy in the neoadjuvant or adjuvant setting if all such treatment was completed > 12 months prior to initiation of study treatment. Participants must comply with all eligibility criteria to be randomized. A. Inclusion Criteria

• Age > 18 years.

• Metastatic or locally advanced unresectable, histologically documented triple-negative breast cancer (TNBC) (absence of HER2-over-expression, ER, and PgR expression by local assessment) o HER2 negativity (it is recommended that labs follow American Society of Clinical Oncology (ASCO)-College of American Pathologists (CAP) HER2 testing guidelines, and interpret as follows) by local laboratory assessment: In situ hybridization non-amplified (ratio of HER2 to CEP17 < 2.0 or single probe average HER2 gene copy number < 4 signals/cell), or IHC 0. o HER2-low-status (it is recommended that labs follow ASCO-CAP HER2 testing guidelines, and interpret as follows) by local laboratory assessment: IHC 2 + and in situ hybridization non-amplified (ratio of HER2 to CEP17 < 2.0 or single probe average HER2 gene copy number < 4 signals/cell), or IHC 1 + (and not required, but if performed, in situ hybridization non-amplified (ratio of HER2 to CEP17 < 2.0 or single probe average HER2 gene copy number < 4 signals/cell)). o ER and PgR negativity are defined as < 1% of cells expressing hormonal receptors via IHC analysis, with testing to be performed locally.

• Measurable disease per RECIST v1 .1 .

• If metastatic disease (Stage IV), measurable disease outside of the bone.

• Previously irradiated lesions can be considered as measurable disease only if disease progression has been unequivocally documented at that same lesion since radiation.

• No prior systemic therapy for metastatic or locally advanced unresectable TNBC. o Radiation therapy for metastatic disease is permitted. There is no required minimum washout period for radiation therapy. Participants should have recovered from the effects of radiation. o Prior systemic therapy for early breast cancer (resectable and non-metastatic, in the neoadjuvant and/or adjuvant setting) is permitted. If prior systemic therapy was given for early TNBC, it must have included anthracycline and taxane. o Prior systemic therapy for early breast cancer is permitted if treatment was completed > 12 months prior to initiation of study treatment (Cycle 1 , Day 1 ). o Prior anti-PD-1 or anti-PD-L1 therapeutic antibody exposure (e.g., atezolizumab or pembrolizumab) in the neoadjuvant and/or adjuvant setting is allowable if treatment was completed > 12 months prior to initiation of study treatment (Cycle 1 , Day 1 ).

• Tumor PD-L1 expression as documented through central testing of a representative tumor tissue specimen. Tumor tissue should be of good quality based on total and viable tumor content and is evaluated at a central laboratory for PD-L1 expression and must be determined to be positive, as determined using: o the investigational VENTANA PD-L1 (SP142) Assay (positive: at least 1% of the tumor area occupied by PD-L1 -expressing tumor-infiltrating immune cells of any intensity (IC > 1%)) o the investigational VENTANA PD-L1 (SP263) Assay (positive: at least 5% of the tumor area occupied by PD-L1 -expressing tumor or tumor-infiltrating immune cells of any intensity (TAP > 5%)) o the investigational Dako PD-L1 IHC 22C3 pharmDx assay (positive: at least 10 of the PD-L1 combined positivity score (CPS > 10)) o positivity by any of these assays is sufficient and required for randomization.

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 .

• Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment: o Absolute neutrophil count (ANC) > 1.5 x 10⁹/L (1500/pL) without granulocyte colonystimulating factor (G-CSF) support within the prior 14 days with one exception: Participants with a benign ethnic neutropenia (BEN): ANC < 1 .3 x 10⁹/L (1300/pL). o Lymphocyte count > 0.5 x 10⁹/L (500/pL) o Platelet count > 100 x 10⁹/L (100,000/pL) without transfusion within the prior 14 days o Hemoglobin > 90 g/L (9 g/dL) without transfusion within the prior 14 days o AST, ALT, and ALP < 2.5 x upper limit of normal (ULN), with the following exceptions:

With documented liver metastases: AST and ALT < 5 x ULN.

With documented liver or bone metastases: ALP < 5 x ULN. o Total bilirubin < 1 .5 x ULN with the following exception:

Known Gilbert disease: total bilirubin < 3 x ULN.

Albumin > 25 g/L (2.5 g/dL). o Not receiving therapeutic anticoagulation: INR and aPTT < 1 .5 x ULN. o Receiving therapeutic anticoagulation: a stable anticoagulant regimen.

• Negative HIV test at screening, with the following exception: individuals with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy, have a CD4 count > 200/pL, and have an undetectable viral load.

• Negative hepatitis B surface antigen (HBsAg) test at screening.

• Positive hepatitis B surface antibody (HBsAb) test at screening, or a negative HBsAb at screening accompanied by either of the following: o Negative hepatitis B core antibody (HBcAb). o Positive HBcAb test followed by quantitative hepatitis B virus (HBV) DNA <500 lU/mL.

• Negative hepatitis C virus (HCV) antibody test at screening, or a positive HCV antibody test followed by a negative HCV RNA test at screening.

• Adequate cardiovascular function: o New York Heart Association (NYHA) Heart Failure Class < 2. o Baseline-corrected QT (QTcF) interval < 480 ms. If the QTcF interval is longer than 480 ms but shorter than 500 ms, the participant may undergo a cardiac evaluation and be considered for treatment in case of no clinically significant findings. o Resting systolic blood pressure < 150 mmHg and diastolic blood pressure 100 mmHg (average of > 3 readings on < 2 sessions with short break between sessions) (or no clinically significant hypertension). o Resting heart rate (HR) between 45 and 100 bpm (or no clinically significant tachycardia). o Left ventricular ejection fraction (LVEF) > 50% assessed by either transthoracic echocardiogram (TTE) or MUGA (TTE preferred test) within 6 months before first study drug administration. o TnT or I (Tnl) < institutional upper limit of normal (ULN). Participants with TnT or Tnl levels between > 1 and < 2 x ULN will be permitted to enter the study if repeat levels are < 1 x ULN. If repeat levels are between > 1 and < 2 x ULN, the participants need to undergo a cardiac evaluation and can be considered for treatment in case of no clinically significant findings.

• For female participants of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception and agree to refrain from donating eggs.

• For male participants: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agree to refrain from donating sperm, as defined below.

B. Exclusion Criteria

• Pregnancy or breastfeeding, or intention of becoming pregnant during the study or within 4 months after the final dose of RO7247669 or pembrolizumab, and 6 months after the final dose of nab-paclitaxel.

• Poor venous access

• Glomerular filtration rate (GFR) < 30 mL/min/1 .73 m² as calculated through use of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. GFR should be assessed by calculation through use of the CKD-EPI equation:

CKD-EPI = 142 x (serum creatinine/ A)^B x 0.9938^Age x (1 .012 if female), where A and B are the following:

■ Female serum creatinine <0.7 mg/dL: A = 0.7 and B =-0.241

■ Female serum creatinine> 0.7 mg/dL: A = 0.7 and B =-1 .2

■ Male serum creatinine < 0.9 mg/dL: A = 0.9 and B = -0.302

■ Male serum creatinine > 0.9 mg/dL: A = 0.9 and B= -1.2

To allow for appropriate nab-paclitaxel dosing, individualized body surface area (BSA) adjusted GFR values should be used (multiply the standardized GFR by the individual’s BSA, calculated using an appropriate formula, and divide by 1 .73).

• History of malignancy within 5 years prior to consent, except for the cancer under investigation in this study and malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate > 90%), such as adequately treated carcinoma in situ of the cervix, nonmelanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.

• Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases. Asymptomatic participants with treated CNS lesions are eligible if all of the following criteria are met:

• Measurable disease, per RECIST v1 .1 , must be present outside the CNS.

• The participant has no history of intracranial hemorrhage or spinal cord hemorrhage. • The participant has not undergone stereotactic radiotherapy within 7 days prior to initiation of study treatment, whole-brain radiotherapy within 14 days prior to initiation of study treatment, or neurosurgical resection within 28 days prior to initiation of study treatment.

• The participant has no ongoing requirement for corticosteroids as therapy for CNS disease.

• If the participant is receiving anti-convulsant therapy, the dose is considered stable (per the investigator’s judgment).

• Metastases are limited to the cerebellum or the supratentorial region (i.e., no metastases to the midbrain, pons, medulla, or spinal cord).

• No evidence of significant vasogenic edema.

• There is no evidence of interim progression (per the investigator’s judgment) between completion of CNS-directed therapy and initiation of study treatment.

• Asymptomatic participants with CNS metastases newly detected at screening are eligible for the study after receiving radiotherapy and/or surgery, with no need to repeat the screening brain scan.

• History of leptomeningeal disease.

• Pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently). Participants with indwelling catheters (e.g., PLEURX®) are allowed.

• Hypercalcemia (ionized calcium > 1 .5 mmol/L, calcium > 12 mg/dL, or corrected calcium > ULN) or hypercalcemia that is symptomatic.

• Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis (granulomatosis with polyangiitis), Sjogren syndrome, Guillain-Barre syndrome, or multiple sclerosis, with the following exceptions: o Participants with a history of autoimmune-related hypothyroidism who are on thyroidreplacement hormone are eligible for the study. o Participants with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study. o Participants with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., participants with psoriatic arthritis are excluded) are eligible for the study provided all following conditions are met:

Rash must cover < 10% of body surface area.

Disease is well-controlled at baseline and requires only low-potency topical corticosteroids.

No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral corticosteroids withinl 2 months prior to consent.

• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug- induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan.

History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

• Active tuberculosis (as defined per local standard of care).

• Significant cardiovascular/cerebrovascular disease within 3 months prior to consent, including any of the following: hypertensive crisis or encephalopathy, unstable angina, transient ischemic attack/stroke, congestive heart failure, serious cardiac arrhythmia requiring treatment (exceptions are atrial fibrillation, paroxysmal supraventricular tachycardia), history of thromboembolic events (such as myocardial infarction, stroke or pulmonary embolism).

• History or presence of an abnormal ECG that is deemed clinically significant, (e.g., complete left bundle branch block, second- or third-degree atrioventricular heart block) or evidence of prior myocardial infarction.

• QT interval corrected through use of Fridericia's formula (QTcF) > 480 ms demonstrated by at least two ECGs > 30 minutes apart. If the QTcF interval is longer than 480 ms but shorter than 500 ms, the participant may undergo a cardiac evaluation and be considered for treatment in case of no clinically significant findings.

• History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as structural heart disease (e.g., severe left ventricular systolic dysfunction, left ventricular hypertrophy), coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic testing), clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden unexplained death or long QT syndrome.

• Major surgical procedure within 4 weeks prior to initiation of study treatment. Placement of central venous access catheter(s) (e.g., port or similar) is not considered a major surgical procedure.

• Treatment with therapeutic oral or IV antimicrobials (anti-bacterial, anti-fungal, anti-viral, anti- parasitic) within 1 week prior to initiation of study treatment. Participants receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease (COPD) exacerbation) are eligible for the study.

• Prior allogeneic stem cell or solid organ transplantation.

• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the participant at high risk from treatment complications.

• Treatment with a live, attenuated vaccine within 28 days prior to initiation of study treatment.

• Prior treatment with CD137 agonists or anti-CTLA therapeutic antibodies or an anti-LAG3 agent.

• Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and IL-2) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment.

• Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including, but not limited to, prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF agents) within 2 weeks prior to initiation of study treatment. o Participants who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea or 48 hours of corticosteroids for a contrast allergy) are eligible for this study. o Participants with a history of allergic reaction to IV contrast requiring steroid pretreatment should have baseline and subsequent tumor assessments performed receiving magnetic resonance imaging (MRI). o The use of inhaled corticosteroids for COPD, mineralocorticoids (e.g., fludrocortisone) for participants with orthostatic hypotension, and low-dose supplemental corticosteroids for adrenocortical insufficiency are allowed.

• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins.

• Known allergy or hypersensitivity to any component of the to nab-paclitaxel formulation.

Example 8: Study Treatment, Other Treatments Relevant to the Study Design, and Concomitant Therapy

Table 14 provides a description of assigned study treatments for the CO44194 study.

Table 14. Study Treatment Description

IMP = investigational medicinal product; NIMP = non-investigational medicinal product.

"Study treatment" refers to the combination of treatments assigned to participants as part of this study (i.e., RO7247669 or pembrolizumab and nab-paclitaxel).

A. Blinded RO7247669 and Blinded Pembrolizumab

Administration of blinded RO7247669 (600 mg Q3W) or blinded pembrolizumab (200 mg Q3W) by IV infusion is performed in a monitored setting where there is immediate access to trained personnel and adequate equipment and medicine to manage potentially serious reactions.

The initial dose is delivered over 60 (±15) minutes. If the 60-minute infusion is tolerated without infusion-associated adverse events (fever or chills), the second infusion may be delivered over 30 (±10) minutes. If the 30-minute infusion is well tolerated, all subsequent infusions may be delivered over 30 (±10) minutes. Participants who experience an infusion-associated adverse event may be premedicated with an antihistamine and/or antipyretic medication for the next infusion, but the infusion time may not be decreased for that infusion.

RO7247669 and pembrolizumab infusions are administered per the instructions outlined in Table 15.

Table 15. Administration of First and Subsequent Infusions of RO7247669 or Pembrolizumab

B. Nab-Paclitaxel The starting dose level of nab-paclitaxel in the study is 100 mg/m² administered intravenously over 30 minutes weekly on a repeating schedule of 3 weeks on followed by 1 week off. Doses of nab- paclitaxel are not administered more frequently than every 7 days.

On days of scheduled infusions of blinded RO7247669 or pembrolizumab and nab-paclitaxel, chemotherapy is to be administered after infusion of RO7247669 or pembrolizumab. Nab-paclitaxel dosing may be adjusted according to the local prescribing information or the E.U.

SmPC in case there is no local approval. Sites follow this labeling guidance for determining the nab- paclitaxel dose for participants who are experiencing obesity and for dose adjustments in the event of participant weight changes. The infusion site is closely monitored for possible infiltration during drug administration.

C. Concomitant Therapy

Permitted Therapy

Use of the following concomitant therapies is permitted as described below:

• Palliative (e.g., treatment of known bone metastases or symptomatic relief of pain) local therapy (e.g., surgery, stereotactic radiosurgery, radiotherapy, radiofrequency ablation) as outlined below:

Palliative local therapy is permitted, provided there has been no unequivocal progression by RECIST v1 .1 . RO7247669 and pembrolizumab may be continued during palliative local therapy.

• Prophylactic or therapeutic anticoagulation therapy (such as warfarin at a stable dose or low- molecular-weight heparin)

• Megestrol acetate administered as an appetite stimulant.

• Mineralocorticoids (e.g., fludrocortisone).

Premedication for nab-paclitaxel is permitted. Premedication with antihistamines, antipyretic medications, and/or analgesics may be administered for the second and subsequent RO7247669 and pembrolizumab infusion only.

In general, a participant’s care is managed with supportive therapies other than those defined as cautionary or prohibited therapies as clinically indicated, per local standard practice. Participants who experience infusion-associated symptoms may be treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or H2-receptor antagonists (e.g., famotidine, cimetidine), or equivalent medications per local standard practice. Serious infusion associated-events manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen saturation, or respiratory distress should be managed with supportive therapies as clinically indicated (e.g., supplemental oxygen and p2- adrenergic agonists).

Cautionary Therapy

Systemic corticosteroids, immunosuppressive medications, and tumor necrosis factor (TNF) inhibitors may attenuate potential beneficial immunologic effects of treatment with RO7247669 and/or pembrolizumab. Therefore, in situations in which systemic corticosteroids, immunosuppressive medications, or TNF inhibitors would be routinely administered, alternatives, including antihistamines, should be considered. If the alternatives are not feasible, systemic corticosteroids, immunosuppressive medications, and TNF inhibitors may be administered at the discretion of the investigator. Systemic corticosteroids or immunosuppressive medications are recommended, at the discretion of the investigator, for the treatment of specific adverse events when associated with RO7247669 and pembrolizumab therapy.

Administering nab-paclitaxel concomitantly with medicines known to induce either CYP2C8 or CYP3A4 (e.g., rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine) is not recommended because efficacy may be compromised because of lower paclitaxel exposures.

Prohibited Therapy

Use of the following concomitant therapies is prohibited as described below:

• Investigational therapy within 28 days prior to initiation of study treatment and during study treatment.

• Concomitant therapy intended for the treatment of cancer (including, but not limited to, chemotherapy, hormonal therapy, immunotherapy, radiotherapy, and herbal therapy), whether health authority-approved or experimental, for various time periods prior to starting study treatment, depending on the agent, and during study treatment, until disease progression is documented and the participant has discontinued study treatment, with the exception of local therapy under certain circumstances.

• Live, attenuated vaccines within 28 day prior to initiation of study treatment, during study treatment, and for 5 months after the final dose of study treatment.

• Systemic immunomodulatory agents (including, but not limited to, interferons and interleukins) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment and during study treatment because these agents could potentially increase the risk for autoimmune conditions when given in combination with study treatment.

Example 9: Study Assessments and Procedures

A. Efficacy Assessments

Tumor and Response Evaluations

Participants in the CO44194 study undergo tumor assessments at screening, every 6 weeks for the first 12 months following treatment initiation, and every 12 weeks thereafter, regardless of dose delays or treatment schedule, until radiographic disease progression according to RECIST v1 .1 . Thus, tumor assessments are to continue according to schedule in participants who discontinue treatment for reasons other than radiographic disease progression per RECIST v1 .1 , withdrawal of consent, death, or study termination, whichever occurs first. In the absence of radiographic disease progression per RECIST v1 .1 , tumor assessments continue regardless of whether a participant starts a follow-up anticancer therapy.

All measurable and/or evaluable lesions are assessed and documented at screening.

Radiographic Assessments

Screening assessments must include CT scans with contrast (per institutional standard operating procedures) of the chest, abdomen, and pelvis. If a CT scan with contrast is contraindicated (e.g., in participants with contrast allergy or impaired renal clearance), a non-contrast CT scan of the chest may be performed and MRI scans (with contrast, if feasible) of the abdomen and pelvis should be performed. Response Evaluation

Objective response within individual participants is determined by the investigator at specified timepoints according to RECIST v1 .1 . Assessments are performed by the same individual, if possible, to ensure internal consistency across visits.

Other endpoints (e.g., ORR, PFS, DOR), are calculated programmatically on the basis of investigator assessments of response at each specified timepoint.

Example 10: Study Assessments and Procedures

A. Statistical Considerations

Statistical Hypotheses

The null (Ho) and alternative (Hi ) hypotheses regarding PFS in the full analysis set (FAS) of the CO44194 study are tested at a one-sided significance level of 0.1 and can be phrased in terms of the population hazard ratio (HR) for PFS, between the experimental arm and the control arm:

HO: A > 1 versus H1 : A < 1

Sample Size Determination

The primary endpoint of progression-free survival (PFS) is analyzed in the FAS. Approximately 160 participants are randomized in a 1 :1 ratio to receive RO7247669 plus nab-paclitaxel or pembrolizumab plus nab-paclitaxel.

The study is powered to approximately 74%, targeting a PFS HR of 0.65 for the primary analysis at an overall alpha of 0.1 (one-sided). Approximately 80 PFS events in the FAS are required for the primary analysis with the following assumptions:

• Median PFS of 9.7 months in the pembrolizumab plus nab-paclitaxel arm.

• Target PFS HR of 0.65.

• One-sided log rank test at the 0.1 level of significance.

• 74% power.

• Drop-out rate of 10% per 12 months.

• Exponential distribution for survival curve of PFS.

• Accrual of approximately 160 patients over 15 months.

With 80 PFS events and a target HR of 0.65, it is projected that an observed HR of 0.751 or less will result in a statistically significant difference between treatment arms (i.e. , HR of 0.751 is the minimal detectable difference (MDD) for the primary analysis). This corresponds to an improvement of 3.2 months in median PFS from 9.7 months in the pembrolizumab plus nab-paclitaxel arm to 12.9 months in the RO7247669 plus nab-paclitaxel arm.

The primary analysis occurs when approximately 80 PFS events have been observed in the FAS and no earlier than 4 months after the last patient is enrolled. The MDD is re-computed for the actual number of PFS events observed at the time of the primary analysis. Table 16 shows the power for several possible true underlying improvements in PFS in favor of RO7247669 plus nab-paclitaxel.

Table 16. Power for Several Possible True Underlying Hazard Ratio Values

a Power is calculated using a one-sided a=0.1

Analysis Sets

The participant analysis sets for the purposes of analyses are defined in Table 17.

Table 17. Participant Analysis Sets

B. Statistical Analyses

General Considerations

The analyses of PFS, ORR and OS are conducted in the FAS, 22C3-positive analysis set,

SP142-positive analysis set, and SP263-positive analysis set. Other efficacy endpoints are assessed in the FAS, unless otherwise specified. Participants are grouped according to the treatment assigned at randomization, regardless of whether they receive any assigned study drug.

Safety analyses are performed on the SAS, unless otherwise specified. Participants are grouped according to the treatment they actually received. Specifically, a participant is classified into the RO7247669 plus nab-paclitaxel arm in the safety analyses if the participant receives any amount of RO7247669, regardless of the initial treatment assignment at randomization.

Estimation Methods for the Primary Endpoint

The primary efficacy endpoint is investigator-assessed PFS in the FAS. The hypothesis test for PFS is conducted at a one-sided significance level of 0.1 .

PFS is defined as the time from randomization to the first occurrence of disease progression as determined by the investigator using RECIST v1 .1 , or death from any cause, whichever occurs first. Data for participants who have not experienced disease progression or death as of the clinical cutoff date are censored at the last tumor assessment date. Participants with no post-baseline tumor assessment are censored at the date of randomization.

PFS is compared between treatment arms using the stratified log-rank test. The HR is estimated using a stratified Cox proportional hazards model. The 95% Cl for the HR is provided. The stratification factors are the same as those used for randomization (i.e., prior cancer immunotherapy exposure and initial presentation of TNBC as de-novo metastatic (Stage IV) disease). Stratification factor(s) may be removed from the stratified analyses if there is risk of over stratification. Results for unstratified analyses are also provided.

Kaplan-Meier methodology will be used to estimate the median PFS (if reached) for each treatment arm, and Kaplan-Meier curves will be produced. The Brookmeyer-Crowley methodology will be used to construct the 95% Cl for the median PFS (if reached) for each treatment arm (Brookmeyer and Crowley 1982).

Estimation Methods for the Secondary Endpoints

PFS in the 22C3-positive analysis set, SP142-positive analysis set, and SP263-positive analysis set is analyzed at the same time with the FAS, using the same methods as described above.

Confirmed ORR is assessed in the FAS, 22C3-positive analysis set, SP142-positive analysis set, and SP263-positive analysis set.

A confirmed objective response is defined as either a complete response (CR) or a partial response (PR) on two consecutive occasions > 4 weeks apart after randomization, as determined by the investigator according to RECIST v1 .1 . Participants not meeting these criteria, including participants without any post-baseline tumor assessment, are considered non-responders.

Confirmed ORR is defined as the proportion of participants who had a confirmed objective response after randomization. ORR is analyzed in participants with measurable disease at baseline and compared between treatment arms using the stratified Cochran Mantel-Haenszel test. The stratification factors are the same as those described for the analysis of the primary endpoint of PFS. Results for unstratified analyses are also provided. The difference in ORR between treatment arms will be calculated, and its 95% Cl will be calculated using the Newcombe method. An estimate of ORR is calculated for each treatment arm, and its 95% Cl is calculated using the Wilson score method.

Duration of response (DOR) is assessed in the FAS. DOR is defined as the time interval from the date of the first occurrence of a confirmed objective response until the first date of progressive disease, as determined by the investigator according to RECIST v1 .1 , or death from any cause, whichever occurs first. DOR is evaluated in the subset of patients with measurable disease at baseline who have achieved a confirmed objective response as determined by the investigator according to RECIST v1 .1 . Data for participants who have not experienced disease progression or death are censored at the last tumor assessment date.

OS is assessed in the FAS, 22C3-positive analysis set, SP142-positive analysis set, and SP263-positive analysis set.

OS is defined as the time from randomization to death from any cause. Data for participants who are not reported as having died by the data cutoff date are censored at the date when they were last known to be alive. Data for participants who do not have post-baseline information are censored at the date of randomization. Methods for comparison of OS between treatment arms are the same as the methods for treatment comparison for the primary endpoint of PFS. Median OS and corresponding 95% Cis (if reached) are estimated using the same methods as for PFS.

The PFS rates at 12 months after randomization are estimated using Kaplan-Meier methodology for each treatment arm, along with 95% Cis calculated using the standard error derived from Greenwood’s formula. The 95% Cl for the difference in PFS rates between the two treatment arms is estimated using the normal approximation method. Similar analyses are performed for the OS rates at 12 months after randomization.

Safety Analyses

Safety analyses include all randomized patients who received at least one dose of study treatment, with patients grouped according to the treatment actually received.

Safety is assessed through summaries of adverse events, changes in laboratory test results, changes in vital signs, study treatment exposures, and is presented by the treatment arm.

Verbatim description of adverse events are mapped to MedDRA thesaurus terms. Severity for all adverse events is graded by the investigator according to the NCI CTCAE v5.0, and severity for CRS is also graded by the investigator according to the American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading scale. All adverse events, serious adverse events, adverse events leading to death, adverse events of special interest, and adverse events leading to study treatment discontinuation that occur on or after the first dose of study treatment (i.e., treatment-emergent adverse events) are summarized by mapped term, appropriate thesaurus level, and severity grade. For events of varying severity, the highest grade is used in the summaries. Deaths and cause of death are summarized.

Relevant laboratory and vital sign data are displayed by time, with grades identified where appropriate. Additionally, a shift table of selected laboratory tests is used to summarize the baseline and maximum postbaseline severity grade. Changes in vital signs are summarized. Pharmacokinetic Analyses

Individual and mean serum RO7247669 concentration versus time data are tabulated and plotted by dose level. The serum pharmacokinetics of RO7247669 are summarized by estimating total exposure (area under the concentration-time curve), maximum observed concentration (serum), total clearance, volume of distribution at steady state, and terminal drug-elimination half-life (as appropriate for data collected). Estimates for these parameters are tabulated and summarized (mean, standard deviation, coefficient of variation, median, and range). Inter-participant variability and drug accumulation are evaluated.

Additional PK analyses are conducted as appropriate.

Paclitaxel pharmacokinetics are tabulated and reported.

Interim Analyses

An interim analysis occurs after approximately 80 randomized patients have a minimum of 3 months of follow-up.

Table 18. Sequences

VIII. Other Embodiments

Some embodiments of the technology described herein can be defined according to any of the following numbered paragraphs:

1 . A method for treating a subject having a cancer (e.g., a non-squamous non-small cell lung cancer (NSCLC)), the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of:

(a) a bispecific antibody targeting PD-1 and LAG3 comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3; and one or more chemotherapeutic agents, e.g.:

(b) an antimetabolite (e.g., pemetrexed); and

(c) a platinum-based chemotherapeutic agent (e.g., carboplatin).

2. The method of paragraph 1 , wherein the method comprises administering to the subject the bispecific antibody at a fixed dose of about 600 mg (e.g., at a fixed dose of 600 mg) every three weeks.

3. The method of paragraph 1 or 2, wherein the method comprises administering to the subject the pemetrexed at a dose of about 500 mg/m² (e.g., at a dose of 500 mg/m²) every three weeks.

4. The method of any one of paragraphs 1 -3, wherein the method comprises administering to the subject the carboplatin at a targeted area under the concentration-time curve (AUC) of about 5 mg/mL • min (e.g., a targeted AUC of 5 mg/mL • min) every three weeks.

5. The method of any one of paragraphs 1 -4, wherein the length of each of the one or more dosing cycles is about 21 days (e.g., is 21 days), and wherein the method comprises administering to the subject the bispecific antibody, the pemetrexed, and the carboplatin or about Day 1 (e.g., Day 1 ±1 day) of each of the one or more dosing cycles.

6. The method of any one of paragraphs 1 -5, wherein the method comprises (a) administering to the subject the bispecific antibody first, the antimetabolite (e.g., pemetrexed) second, and the platinum-based chemotherapeutic agent (e.g., carboplatin) third, or (b) administering to the subject the antimetabolite (e.g., pemetrexed) first, the platinum-based chemotherapeutic agent (e.g., carboplatin) second, and the bispecific antibody third. 7. The method of any one of paragraphs 1 -6, wherein the method comprises administering to the subject the bispecific antibody, the antimetabolite (e.g., pemetrexed), and the platinum-based chemotherapeutic agent (e.g., carboplatin) intravenously.

8. The method of paragraph 7, wherein:

(a) the bispecific antibody is administered over 60 (± 15) minutes in a first dosing cycle;

(b) the method comprises one or more additional dosing cycles, and the bispecific antibody is administered over 30 (± 10) minutes in the one or more additional dosing cycles;

(c) the antimetabolite (e.g., pemetrexed) is administered over 10 minutes; and/or

(d) the platinum-based chemotherapeutic agent (e.g., carboplatin) is administered over 30-60 minutes.

9. The method of any one of paragraphs 1 -8, wherein the dosing regimen comprises four dosing cycles.

10. The method of any one of paragraphs 1 -9, wherein the dosing regimen further comprises one or more additional dosing cycles of (a) the bispecific antibody and (b) the antimetabolite (e.g., pemetrexed).

11 . The method of paragraph 10, wherein the dosing regimen comprises at least 5 or at least 10 additional dosing cycles of (a) the bispecific antibody and (b) the antimetabolite (e.g., pemetrexed).

12. A method for treating a subject having a cancer (e.g., a squamous NSCLC), the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of:

(b) a taxane (e.g., paclitaxel); and

(c) a platinum-based chemotherapeutic agent (e.g., carboplatin).

13. The method of paragraph 12, wherein the method comprises administering to the subject the bispecific antibody at a fixed dose of about 600 mg (e.g., at a fixed dose of 600 mg) every three weeks.

14. The method of paragraph 12 or 13, wherein the method comprises administering to the subject the paclitaxel at a dose of about 200 mg/m² (e.g., a dose of 200 mg/m²) every three weeks.

15. The method of any one of paragraphs 12-14, wherein the method comprises administering to the subject the carboplatin at a targeted AUC of about 5 mg/mL • min (e.g., a targeted AUC of 5 mg/mL • min) every three weeks.

16. The method of any one of paragraphs 12-15, wherein the length of each of the one or more dosing cycles is about 21 days (e.g., is 21 days), and wherein the method comprises administering to the subject the bispecific antibody, the taxane (e.g., paclitaxel), and the platinum-based chemotherapeutic agent (e.g., carboplatin) or about Day 1 (e.g., Day 1 ±1 day) of each of the one or more dosing cycles.

17. The method of any one of paragraphs 12-16, wherein the method comprises (a) administering to the subject the bispecific antibody first, the taxane (e.g., paclitaxel) second, and the platinum-based chemotherapeutic agent (e.g., carboplatin) third, or (b) administering to the subject the taxane (e.g., paclitaxel) first, the platinum-based chemotherapeutic agent (e.g., carboplatin) second, and the bispecific antibody third.

18. The method of any one of paragraphs 12-17, wherein the method comprises administering to the subject the bispecific antibody, the taxane (e.g., paclitaxel), and the platinum-based chemotherapeutic agent (e.g., carboplatin) intravenously.

19. The method of paragraph 18, wherein:

(c) the taxane (e.g., paclitaxel) is administered over 3 hours; and/or

20. The method of any one of paragraphs 12-19, wherein the dosing regimen comprises four dosing cycles.

21 . The method of any one of paragraphs 12-20, wherein the dosing regimen further comprises one or more additional dosing cycles of the bispecific antibody.

22. The method of paragraph 21 , wherein the dosing regimen comprises at least 5 or at least 10 additional dosing cycles of the bispecific antibody.

23. The method of any one of paragraphs 12-22, wherein the subject is premedicated with an oral or IV steroid and antihistamines prior to administration of the taxane (e.g., paclitaxel).

24. The method of any one of paragraphs 1 -23, wherein the cancer is Stage IIIB/IIIC or Stage IV (e.g., the NSCLC is:

(a) a Stage IIIB/IIIC NSCLC; or

(b) a Stage IV NSCLC).

25. The method of any one of paragraphs 1 -24, wherein the subject has not received prior systemic treatment for metastatic cancer (e.g., metastatic NSCLC). 26. The method of any one of paragraphs 1 -25, wherein the subject has not previously been treated with an immune checkpoint blockade therapy.

27. The method of any one of paragraphs 1 -26, wherein the subject has not previously been treated with an anti-cytotoxic T lymphocyte-associated protein 4 (CTLA4) agent, an anti-T cell immunoreceptor with Ig and tyrosine-based inhibition motif domains (TIG IT) agent, an anti-PD-1 therapeutic antibody, an anti-PD-L1 therapeutic antibody, or an anti-LAG3 agent.

28. The method of any one of paragraphs 1 -27, wherein the subject has not previously been treated with a CD137 agonist.

29. The method of any one of paragraphs 1 -28, wherein the subject does not have any symptomatic, untreated, or actively progressing central nervous system (CNS) metastases.

30. The method of any one of paragraphs 1 -29, wherein the subject does not have a known mutation in the epidermal growth factor receptor (EGFR) gene or an anaplastic lymphoma kinase (ALK) fusion oncogene.

31 . The method of any one of paragraphs 1 -30, wherein the subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 .

32. The method of any one of paragraphs 1 -31 , wherein a tumor sample from the cancer (e.g., NSCLC) of the subject has a PD-L1 tumor proportion score (TPS) or a PD-L1 expression level on tumor cells (TCs) of <1%.

33. The method of any one of paragraphs 1 -31 , wherein a tumor sample from the cancer (e.g., NSCLC) of the subject has a PD-L1 TPS or a PD-L1 expression level on TCs of between 1 % and 49%.

34. The method of any one of paragraphs 1 -31 , wherein a tumor sample from the cancer (e.g., NSCLC) of the subject has a PD-L1 TPS or a PD-L1 expression level on TCs of >50%.

35. The method of any one of paragraphs 1 -34, wherein the method results in an increase in progression-free survival (PFS) as compared to a reference PFS.

36. The method of paragraph 35, wherein the reference PFS is a PFS of a population of subjects who have received a control therapy.

37. The method of any one of paragraphs 1 -36, wherein the method results in an increase in objective response rate (ORR) in a population of subjects treated according to the method as compared to a reference ORR. 38. The method of paragraph 37, wherein the reference ORR is an ORR of a population of subjects who have received a control therapy.

39. The method of any one of paragraphs 1 -38, wherein the method results in an increase in overall survival (OS) as compared to a reference OS.

40. The method of paragraph 39, wherein the reference OS is an OS of a population of subjects who have received a control therapy.

41 . The method of any one of paragraphs 1 -40, wherein the method results in an increase in duration of response (DOR) as compared to a reference DOR.

42. The method of paragraph 41 , wherein the reference DOR is a DOR of a population of subjects who have received a control therapy.

43. The method of any one of paragraphs 36-42, wherein:

(a) the control therapy comprises pembrolizumab, an antimetabolite (e.g., pemetrexed), and a platinum-based chemotherapeutic agent (e.g., carboplatin) and does not comprise the bispecific antibody (e.g., the subject has a non-squamous NSCLC, and the control therapy comprises pembrolizumab, an antimetabolite (e.g., pemetrexed), and a platinum-based chemotherapeutic agent (e.g., carboplatin) and does not comprise the bispecific antibody); or

(b) the control therapy comprises pembrolizumab, a taxane (e.g., paclitaxel), and a platinum-based chemotherapeutic agent (e.g., carboplatin) and does not comprise the bispecific antibody (e.g., the subject has a squamous NSCLC, and the control therapy comprises pembrolizumab, a taxane (e.g., paclitaxel), and a platinum-based chemotherapeutic agent (e.g., carboplatin) and does not comprise the bispecific antibody).

44. The method of any one of paragraphs 1 -43, wherein the bispecific antibody targeting PD-1 and LAG3 comprises a first antigen-binding domain that specifically binds to PD-1 comprising a heavy chain variable (VH) domain comprising:

(ii) an HVR-H2 sequence comprising the amino acid sequence GGR, and

(i) an HVR-L1 sequence comprising the amino acid sequence of SEQ ID NO: 3;

(ii) an HVR-L2 sequence comprising the amino acid sequence RSS, and

(iii) an HVR-L3 sequence comprising the amino acid sequence of SEQ ID NO: 4.

45. The method of paragraph 44, wherein the bispecific antibody targeting PD-1 and LAG3 comprises a Fc domain that is an IgG. 46. The method of paragraph 45, wherein the IgG Fc domain is an IgG 1 Fc domain or an lgG4 Fc domain.

47. The method of paragraph 45 or 46, wherein the Fc domain comprises one or more amino acid substitutions that reduce binding to an Fc receptor.

48. The method of paragraph 47, wherein the Fc receptor is an Fey receptor.

49. The method of any one of paragraphs 44-48, wherein the bispecific antibody targeting PD-1 and LAG3 comprises a second antigen-binding domain that specifically binds to LAG3 comprising a VH domain comprising:

(i) an HVR-H1 sequence comprising the amino acid sequence of SEQ ID NO: 7,

(ii) an HVR-H2 sequence comprising the amino acid sequence of SEQ ID NO: 8, and (Hi) an HVR-H3 sequence comprising an amino acid sequence of SEQ ID NO: 9; and a VL domain comprising:

(i) an HVR-L1 sequence comprising the amino acid sequence of SEQ ID NO: 10,

(ii) an HVR-L2 sequence comprising the amino acid sequence of SEQ ID NO: 11 , and (Hi) an HVR-L3 sequence comprising the amino acid sequence of SEQ ID NO: 12.

50. The method of any one of paragraphs 44-49, wherein the first antigen-binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 5 and a VL domain comprising the amino acid sequence of SEQ ID NO: 6, and the second antigen-binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 13 and a VL domain comprising the amino acid sequence of SEQ ID NO: 14.

51 . The method of any one of paragraphs 44-50, wherein the bispecific antibody targeting PD-1 and LAG3 comprises:

52. The method of any one of paragraphs 45-51 , wherein the first subunit of the Fc domain comprises the amino acid substitutions S354C and T366W (numbering according to Kabat EU index) and the second subunit of the Fc domain comprises the amino acid substitutions Y349C, T366S, and Y407V (numbering according to Kabat EU index).

53. The method of any one of paragraphs 44-52, wherein the bispecific antibody targeting PD-1 and LAG3 comprises a first Fab fragment comprising said first antigen binding domain specifically binding to PD1 comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 5 and a VL domain comprising the amino acid sequence of SEQ ID NO: 6, and a second Fab fragment comprising the second antigen binding domain specifically binding to LAG3 comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 13 and a VL domain comprising the amino acid sequence of SEQ ID NO: 14, and an Fc domain of human IgG 1 subclass with the amino acid mutations L234A, L235A, and P329G (numbering according to Kabat EU index).

54. The method of paragraph 53, wherein in one of the Fab fragments of the bispecific antibody targeting PD-1 and LAG3 the variable domains VL and VH are replaced by each other so that the VH domain is part of the light chain and the VL domain is part of the heavy chain.

55. The method of paragraph 54, wherein in the first Fab fragment the variable domains VL and VH are replaced by each other.

56. The method of any one of paragraphs 53-55, wherein in the constant domain CL of one of the Fab fragments the amino acid at position 124 is substituted independently by lysine (K), arginine (R), or histidine (H) (numbering according to Kabat EU Index), and in the constant domain CH1 the amino acids at positions 147 and 213 are substituted independently by glutamic acid (E) or aspartic acid (D) (numbering according to Kabat EU index).

57. The method of paragraph 56, wherein in the constant domain CL of the second Fab fragment the amino acid at position 124 is substituted independently by lysine (K), arginine (R), or histidine (H) (numbering according to Kabat EU Index), and in the constant domain CH1 the amino acids at positions 147 and 213 are substituted independently by glutamic acid (E) or aspartic acid (D) (numbering according to Kabat EU index).

58. The method of any one of paragraphs 44-57, wherein the bispecific antibody comprises a first heavy chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 15, a first light chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 16, a second heavy chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 17, and a second light chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 18.

59. The method of paragraph 58, wherein the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 15, a first light chain comprising the amino acid sequence of SEQ ID NO: 16, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 17, and a second light chain comprising the amino acid sequence of SEQ ID NO: 18. 60. A method for treating a subject having a cancer (e.g., a non-squamous Stage IIIB/IIIC NSCLC or a Stage IV NSCLC), the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of:

(1 )

(a) a bispecific antibody targeting PD-1 and LAG3 comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, wherein the method comprises administering to the subject the bispecific antibody at a fixed dose of 600 mg every three weeks, and wherein the bispecific antibody comprises: a first heavy chain comprising the amino acid sequence of SEQ ID NO: 15, a first light chain comprising the amino acid sequence of SEQ ID NO: 16, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 17, and a second light chain comprising the amino acid sequence of SEQ ID NO: 18;

(b) an antimetabolite (e.g., pemetrexed), wherein, in aspects in which the antimetabolite is pemetrexed, the method comprises administering to the subject the pemetrexed at a dose of 500 mg/m² every three weeks; and

(c) a platinum-based chemotherapeutic agent (e.g., carboplatin), wherein, in aspects in which the platinum-based chemotherapeutic agent is carboplatin, the method comprises administering to the subject the carboplatin at a targeted area under the concentration-time curve (AUC) of 5 mg/mL • min every three weeks; or

(2)

(a) a bispecific antibody targeting PD-1 and LAG3 comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, wherein the method comprises administering to the subject the bispecific antibody at a fixed dose of 600 mg every three weeks, and wherein the bispecific antibody comprises:

(i) a first antigen-binding domain that specifically binds to PD-1 , comprising the following hypervariable regions (HVRs): an HVR-H1 sequence comprising the amino acid sequence of SEQ ID NO: 1 , an HVR-H2 sequence comprising the amino acid sequence GGR, an HVR-H3 sequence comprising an amino acid sequence of SEQ ID NO: 2; an HVR-L1 sequence comprising the amino acid sequence of SEQ ID NO: 3; an HVR-L2 sequence comprising the amino acid sequence RSS, and an HVR-L3 sequence comprising the amino acid sequence of SEQ ID NO: 4; and

(ii) a second antigen-binding domain that specifically binds to LAG3, comprising the following HVRs: an HVR-H1 sequence comprising the amino acid sequence of SEQ ID NO: 7, an HVR-H2 sequence comprising the amino acid sequence of SEQ ID NO: 8, an HVR-H3 sequence comprising an amino acid sequence of SEQ ID NO: 9; an HVR-L1 sequence comprising the amino acid sequence of SEQ ID NO: 10, an HVR-L2 sequence comprising the amino acid sequence of SEQ ID NO: 11 , and an HVR-L3 sequence comprising the amino acid sequence of SEQ ID NO: 12; (b) an antimetabolite (e.g., pemetrexed), wherein, in aspects in which the antimetabolite is pemetrexed, the method comprises administering to the subject the pemetrexed at a dose of 500 mg/m² every three weeks; and

(c) a platinum-based chemotherapeutic agent (e.g., carboplatin), wherein, in aspects in which the platinum-based chemotherapeutic agent is carboplatin, the method comprises administering to the subject the carboplatin at a targeted area under the concentration-time curve (AUC) of 5 mg/mL • min every three weeks.

61 . A method for treating a subject having a cancer (e.g., a squamous Stage IIIB/IIIC NSCLC or a Stage IV NSCLC), the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of:

(1 )

(b) a taxane (e.g., paclitaxel), wherein, in aspects in which the taxane is paclitaxel, the method comprises administering to the subject the paclitaxel at a dose of 200 mg/m² every three weeks; and

(c) a platinum-based chemotherapeutic agent (e.g., carboplatin), wherein, in aspects in which the platinum-based chemotherapeutic agent is carboplatin, the method comprises administering to the subject the carboplatin at a targeted AUC of 5 mg/mL • min every three weeks; or

(2)

(i) a first antigen-binding domain that specifically binds to PD-1 , comprising the following HVRs: an HVR-H1 sequence comprising the amino acid sequence of SEQ ID NO: 1 , an HVR-H2 sequence comprising the amino acid sequence GGR, an HVR-H3 sequence comprising an amino acid sequence of SEQ ID NO: 2; an HVR-L1 sequence comprising the amino acid sequence of SEQ ID NO: 3; an HVR-L2 sequence comprising the amino acid sequence RSS, and an HVR-L3 sequence comprising the amino acid sequence of SEQ ID NO: 4; and

(ii) a second antigen-binding domain that specifically binds to LAG3, comprising the following HVRs: an HVR-H1 sequence comprising the amino acid sequence of SEQ ID NO: 7, an HVR-H2 sequence comprising the amino acid sequence of SEQ ID NO: 8, an HVR-H3 sequence comprising an amino acid sequence of SEQ ID NO: 9; an HVR-L1 sequence comprising the amino acid sequence of SEQ ID NO: 10, an HVR-L2 sequence comprising the amino acid sequence of SEQ ID NO: 11 , and an HVR-L3 sequence comprising the amino acid sequence of SEQ ID NO: 12;

(c) a platinum-based chemotherapeutic agent (e.g., carboplatin), wherein, in aspects in which the platinum-based chemotherapeutic agent is carboplatin, the method comprises administering to the subject the carboplatin at a targeted AUC of 5 mg/mL • min every three weeks.

62. The method of any one of paragraphs 1 -61 , wherein the subject is a human.

63. A bispecific antibody targeting PD-1 and LAG3 for use in a method of treating a subject having a cancer (e.g., a non-squamous non-small cell lung cancer (NSCLC)), wherein the method comprises a dosing regimen comprising a bispecific antibody targeting PD-1 and LAG3 and one or more chemotherapeutic agents, wherein the bispecific antibody comprises a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, and wherein the dosing regimen comprises administering to the subject one or more dosing cycles of:

(a) the bispecific antibody; and the one or more chemotherapeutic agents, e.g.:

(b) an antimetabolite (e.g., pemetrexed); and

(c) a platinum-based chemotherapeutic agent (e.g., carboplatin).

64. The bispecific antibody for use of paragraph 63, wherein the method comprises administering to the subject the bispecific antibody at a fixed dose of about 600 mg (e.g., at a fixed dose of 600 mg) every three weeks.

65. The bispecific antibody for use of paragraph 63 or 64, wherein the method comprises administering to the subject the pemetrexed at a dose of about 500 mg/m² (e.g., at a dose of 500 mg/m²) every three weeks.

66. The bispecific antibody for use of any one of paragraphs 63-65, wherein the method comprises administering to the subject the carboplatin at a targeted area under the concentration-time curve (AUC) of about 5 mg/mL • min (e.g., a targeted AUC of 5 mg/mL • min) every three weeks.

67. The bispecific antibody for use of any one of paragraphs 63-66, wherein the length of each of the one or more dosing cycles is about 21 days (e.g., is 21 days), and wherein the method comprises administering to the subject the bispecific antibody, the pemetrexed, and the carboplatin or about Day 1 (e.g., Day 1 ±1 day) of each of the one or more dosing cycles. 68. The bispecific antibody for use of any one of paragraphs 63-67, wherein the method comprises (a) administering to the subject the bispecific antibody first, the antimetabolite (e.g., pemetrexed) second, and the platinum-based chemotherapeutic agent (e.g., carboplatin) third, or (b) administering to the subject the antimetabolite (e.g., pemetrexed) first, the platinum-based chemotherapeutic agent (e.g., carboplatin) second, and the bispecific antibody third.

69. The bispecific antibody for use of any one of paragraphs 63-68, wherein the method comprises administering to the subject the bispecific antibody, the antimetabolite (e.g., pemetrexed), and the platinum-based chemotherapeutic agent (e.g., carboplatin) intravenously.

70. The bispecific antibody for use of paragraph 69, wherein:

(a) the bispecific antibody is to be administered over 60 (± 15) minutes in a first dosing cycle;

(b) the method comprises one or more additional dosing cycles, and the bispecific antibody is to be administered over 30 (± 10) minutes in the one or more additional dosing cycles;

71 . The bispecific antibody for use of any one of paragraphs 63-70, wherein the dosing regimen comprises four dosing cycles.

72. The bispecific antibody for use of any one of paragraphs 63-71 , wherein the dosing regimen further comprises one or more additional dosing cycles of (a) the bispecific antibody and (b) the antimetabolite (e.g., pemetrexed).

73. The bispecific antibody for use of paragraph 72, wherein the dosing regimen comprises at least 5 or at least 10 additional dosing cycles of (a) the bispecific antibody and (b) the antimetabolite (e.g., pemetrexed).

74. A bispecific antibody targeting PD-1 and LAG3 for use in a method of treating a subject having a cancer (e.g., a squamous NSCLC), wherein the method comprises a dosing regimen comprising a bispecific antibody targeting PD-1 and LAG3 and one or more chemotherapeutic agents , wherein the bispecific antibody comprises a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, and wherein the dosing regimen comprises administering to the subject one or more dosing cycles of:

(a) the bispecific antibody; and the one or more chemotherapeutic agents, e.g.:

(b) a taxane (e.g., paclitaxel); and

(c) a platinum-based chemotherapeutic agent (e.g., carboplatin).

75. The bispecific antibody for use of paragraph 74, wherein the method comprises administering to the subject the bispecific antibody at a fixed dose of about 600 mg (e.g., at a fixed dose of 600 mg) every three weeks. 76. The bispecific antibody for use of paragraph 74 or 75, wherein the method comprises administering to the subject the paclitaxel at a dose of about 200 mg/m² (e.g., a dose of 200 mg/m²) every three weeks.

77. The bispecific antibody for use of any one of paragraphs 74-76, wherein the method comprises administering to the subject the carboplatin at a targeted AUC of about 5 mg/mL • min (e.g., a targeted AUC of 5 mg/mL • min) every three weeks.

78. The bispecific antibody for use of any one of paragraphs 74-77, wherein the length of each of the one or more dosing cycles is about 21 days (e.g., is 21 days), and wherein the method comprises administering to the subject the bispecific antibody, the taxane (e.g., paclitaxel), and the platinum-based chemotherapeutic agent (e.g., carboplatin) on or about Day 1 (e.g., Day 1 ±1 day) of each of the one or more dosing cycles.

79. The bispecific antibody for use of any one of paragraphs 74-78, wherein the method comprises (a) administering to the subject the taxane (e.g., paclitaxel) second, and the platinum-based chemotherapeutic agent (e.g., carboplatin) third, or (b) administering to the subject the taxane (e.g., paclitaxel) first, the platinum-based chemotherapeutic agent (e.g., carboplatin) second, and the bispecific antibody third.

80. The bispecific antibody for use of any one of paragraphs 74-79, wherein the method comprises administering to the subject the taxane (e.g., paclitaxel), and the platinum-based chemotherapeutic agent (e.g., carboplatin) intravenously.

81 . The bispecific antibody for use of paragraph 80, wherein:

(c) the taxane (e.g., paclitaxel) is administered over 3 hours; and/or

82. The bispecific antibody for use of any one of paragraphs 74-80, wherein the dosing regimen comprises four dosing cycles.

83. The bispecific antibody for use of any one of paragraphs 74-82, wherein the dosing regimen further comprises one or more additional dosing cycles of the bispecific antibody.

84. The bispecific antibody for use of paragraph 83, wherein the dosing regimen comprises at least 5 or at least 10 additional dosing cycles of the bispecific antibody. 85. The bispecific antibody for use of any one of paragraphs 74-84, wherein the subject is to be premedicated with an oral or IV steroid and antihistamines prior to administration of the taxane (e.g., paclitaxel).

86. The bispecific antibody for use of any one of paragraphs 63-85, wherein the cancer is Stage IIIB/IIIC or Stage IV (e.g., the NSCLC is:

(a) a Stage IIIB/IIIC NSCLC; or

(b) a Stage IV NSCLC).

87. The bispecific antibody for use of any one of paragraphs 63-86, wherein the subject has not received prior systemic treatment for metastatic cancer (e.g., metastatic NSCLC).

88. The bispecific antibody for use of any one of paragraphs 63-87, wherein the subject has not previously been treated with an immune checkpoint blockade therapy.

89. The bispecific antibody for use of any one of paragraphs 63-88, wherein the subject has not previously been treated with an anti-cytotoxic T lymphocyte-associated protein 4 (CTLA4) agent, an anti-T cell immunoreceptor with Ig and tyrosine-based inhibition motif domains (TIGIT) agent, an anti-PD-1 therapeutic antibody, an anti-PD-L1 therapeutic antibody, or an anti-LAG3 agent.

90. The bispecific antibody for use of any one of paragraphs 63-89, wherein the subject has not previously been treated with a CD137 agonist.

91 . The bispecific antibody for use of any one of paragraphs 63-90, wherein the subject does not have any symptomatic, untreated, or actively progressing central nervous system (CNS) metastases.

92. The bispecific antibody for use of any one of paragraphs 63-91 , wherein the subject does not have a known mutation in the epidermal growth factor receptor (EGFR) gene or an anaplastic lymphoma kinase (ALK) fusion oncogene.

93. The bispecific antibody for use of any one of paragraphs 63-92, wherein the subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 .

94. The bispecific antibody for use of any one of paragraphs 63-93, wherein a tumor sample from the cancer (e.g., NSCLC) of the subject has a PD-L1 tumor proportion score (TPS) or a PD-L1 expression level on tumor cells (TCs) of <1%.

95. The bispecific antibody for use of any one of paragraphs 63-93, wherein a tumor sample from the cancer (e.g., NSCLC) of the subject has a PD-L1 TPS or a PD-L1 expression level on TCs of between 1 % and 49%. 96. The bispecific antibody for use of any one of paragraphs 63-93, wherein a tumor sample from the cancer (e.g., NSCLC) of the subject has a PD-L1 TPS or a PD-L1 expression level on TCs of >50%.

97. The bispecific antibody for use of any one of paragraphs 63-96, wherein the method results in an increase in progression-free survival (PFS) as compared to a reference PFS.

98. The bispecific antibody for use of paragraph 97, wherein the reference PFS is a PFS of a population of subjects who have received a control therapy.

99. The bispecific antibody for use of any one of paragraphs 63-98, wherein the method results in an increase in objective response rate (ORR) in a population of subjects treated according to the method as compared to a reference ORR.

100. The bispecific antibody for use of paragraph 99, wherein the reference ORR is an ORR of a population of subjects who have received a control therapy.

101 . The bispecific antibody for use of any one of paragraphs 63-100, wherein the method results in an increase in overall survival (OS) as compared to a reference OS.

102. The bispecific antibody for use of paragraph 101 , wherein the reference OS is an OS of a population of subjects who have received a control therapy.

103. The bispecific antibody for use of any one of paragraphs 63-102, wherein the method results in an increase in duration of response (DOR) as compared to a reference DOR.

104. The bispecific antibody for use of paragraph 103, wherein the reference DOR is a DOR of a population of subjects who have received a control therapy.

105. The bispecific antibody for use of any one of paragraphs 98-104, wherein:

106. The bispecific antibody for use of any one of paragraphs 63-105, wherein the bispecific antibody targeting PD-1 and LAG3 comprises a first antigen-binding domain that specifically binds to PD-1 comprising a heavy chain variable (VH) domain comprising:

(ii) an HVR-H2 sequence comprising the amino acid sequence GGR, and

(i) an HVR-L1 sequence comprising the amino acid sequence of SEQ ID NO: 3;

(ii) an HVR-L2 sequence comprising the amino acid sequence RSS, and

(iii) an HVR-L3 sequence comprising the amino acid sequence of SEQ ID NO: 4.

107. The bispecific antibody for use of paragraph 106, wherein the bispecific antibody targeting PD-1 and LAG3 comprises a Fc domain that is an IgG.

108. The bispecific antibody for use of paragraph 107, wherein the IgG Fc domain is an IgG 1 Fc domain or an lgG4 Fc domain.

109. The bispecific antibody for use of paragraph 107 or 108, wherein the Fc domain comprises one or more amino acid substitutions that reduce binding to an Fc receptor.

110. The bispecific antibody for use of paragraph 109, wherein the Fc receptor is an Fey receptor.

111. The bispecific antibody for use of any one of paragraphs 106-110, wherein the bispecific antibody targeting PD-1 and LAG3 comprises a second antigen-binding domain that specifically binds to LAG3 comprising a VH domain comprising:

(i) an HVR-H1 sequence comprising the amino acid sequence of SEQ ID NO: 7,

(ii) an HVR-H2 sequence comprising the amino acid sequence of SEQ ID NO: 8, and

(i) an HVR-L1 sequence comprising the amino acid sequence of SEQ ID NO: 10,

(iii) an HVR-L3 sequence comprising the amino acid sequence of SEQ ID NO: 12.

112. The bispecific antibody for use of any one of paragraphs 106-111 , wherein the first antigen-binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 5 and a VL domain comprising the amino acid sequence of SEQ ID NO: 6, and the second antigen-binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 13 and a VL domain comprising the amino acid sequence of SEQ ID NO: 14.

113. The bispecific antibody for use of any one of paragraphs 106-112, wherein the bispecific antibody targeting PD-1 and LAG3 comprises: (a) an Fc domain of human IgG 1 subclass with the amino acid mutations L234A, L235A, and P329G (numbering according to Kabat EU index); and/or

1 14. The bispecific antibody for use of any one of paragraphs 107-1 13, wherein the first subunit of the Fc domain comprises the amino acid substitutions S354C and T366W (numbering according to Kabat EU index) and the second subunit of the Fc domain comprises the amino acid substitutions Y349C, T366S, and Y407V (numbering according to Kabat EU index).

1 15. The bispecific antibody for use of any one of paragraphs 106-1 14, wherein the bispecific antibody targeting PD-1 and LAG3 comprises a first Fab fragment comprising said first antigen binding domain specifically binding to PD1 comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 5 and a VL domain comprising the amino acid sequence of SEQ ID NO: 6, and a second Fab fragment comprising the second antigen binding domain specifically binding to LAG3 comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 13 and a VL domain comprising the amino acid sequence of SEQ ID NO: 14, and an Fc domain of human IgG 1 subclass with the amino acid mutations L234A, L235A, and P329G (numbering according to Kabat EU index).

1 16. The bispecific antibody for use of paragraph 1 15, wherein in one of the Fab fragments of the bispecific antibody targeting PD-1 and LAG3 the variable domains VL and VH are replaced by each other so that the VH domain is part of the light chain and the VL domain is part of the heavy chain.

1 17. The bispecific antibody for use of paragraph 116, wherein in the first Fab fragment the variable domains VL and VH are replaced by each other.

1 18. The bispecific antibody for use of any one of paragraphs 1 15-1 17, wherein in the constant domain CL of one of the Fab fragments the amino acid at position 124 is substituted independently by lysine (K), arginine (R), or histidine (H) (numbering according to Kabat EU Index), and in the constant domain CH1 the amino acids at positions 147 and 213 are substituted independently by glutamic acid (E) or aspartic acid (D) (numbering according to Kabat EU index).

1 19. The bispecific antibody for use of paragraph 118, wherein in the constant domain CL of the second Fab fragment the amino acid at position 124 is substituted independently by lysine (K), arginine (R), or histidine (H) (numbering according to Kabat EU Index), and in the constant domain CH1 the amino acids at positions 147 and 213 are substituted independently by glutamic acid (E) or aspartic acid (D) (numbering according to Kabat EU index). 120. The bispecific antibody for use of any one of paragraphs 106-119, wherein the bispecific antibody comprises a first heavy chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 15, a first light chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 16, a second heavy chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 17, and a second light chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 18.

121 . The bispecific antibody for use of paragraph 120, wherein the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 15, a first light chain comprising the amino acid sequence of SEQ ID NO: 16, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 17, and a second light chain comprising the amino acid sequence of SEQ ID NO: 18.

122. A bispecific antibody targeting PD-1 and LAG3 for use in a method of treating a subject having a non-squamous Stage IIIB/IIIC NSCLC or a Stage IV NSCLC, wherein the method comprises a dosing regimen comprising a bispecific antibody targeting PD-1 and LAG3 and one or more chemotherapeutic agents, wherein the bispecific antibody comprises a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, and wherein the dosing regimen comprises administering to the subject one or more dosing cycles of:

(1 )

(2)

(a) a bispecific antibody targeting PD-1 and LAG3 comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, wherein the method comprises administering to the subject the bispecific antibody at a fixed dose of 600 mg every three weeks, and wherein the bispecific antibody comprises: (i) a first antigen-binding domain that specifically binds to PD-1 , comprising the following hypervariable regions (HVRs): an HVR-H1 sequence comprising the amino acid sequence of SEQ ID NO: 1 , an HVR-H2 sequence comprising the amino acid sequence GGR, an HVR-H3 sequence comprising an amino acid sequence of SEQ ID NO: 2; an HVR-L1 sequence comprising the amino acid sequence of SEQ ID NO: 3; an HVR-L2 sequence comprising the amino acid sequence RSS, and an HVR-L3 sequence comprising the amino acid sequence of SEQ ID NO: 4; and

123. A bispecific antibody targeting PD-1 and LAG3 for use in a method of treating a subject having a squamous Stage IIIB/IIIC NSCLC or a Stage IV NSCLC, wherein the method comprises a dosing regimen comprising a bispecific antibody targeting PD-1 and LAG3 and one or more chemotherapeutic agents, wherein the bispecific antibody comprises a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, and wherein the dosing regimen comprises administering to the subject one or more dosing cycles of:

(1 )

(b) a taxane (e.g., paclitaxel), wherein, in aspects in which the taxane is paclitaxel, the method comprises administering to the subject the paclitaxel at a dose of 200 mg/m² every three weeks; and (c) a platinum-based chemotherapeutic agent (e.g., carboplatin), wherein, in aspects in which the platinum-based chemotherapeutic agent is carboplatin, the method comprises administering to the subject the carboplatin at a targeted AUC of 5 mg/mL • min every three weeks; or

(2)

124. The bispecific antibody for use of any one of paragraphs 63-123, wherein the subject is a human.

125. A method for treating a subject having a cancer (e.g., a triple-negative breast cancer (TNBC)), wherein the method comprises a dosing regimen comprising concurrently administering to the subject:

(a) one or more dosing cycles of a bispecific antibody targeting PD-1 and LAG3 comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3; and

(b) one or more dosing cycles of a chemotherapeutic agent (e.g., a taxane, e.g., nab-paclitaxel).

126. The method of paragraph 125, wherein the subject has not previously received a systemic anticancer therapy for locally advanced, unresectable or metastatic cancer (e.g., TNBC). 127. The method of paragraph 125 or 126, wherein the subject has not previously been treated with an anti-LAG3 therapy, a CD137 agonist, or an anti-CTLA therapeutic antibody.

128. The method of any one of paragraphs 125-127, wherein the method comprises administering to the subject the bispecific antibody at a fixed dose of about 600 mg (e.g., at a fixed dose of 600 mg) every three weeks.

129. The method of any one of paragraphs 125-128, wherein the length of each of the one or more dosing cycles of the bispecific antibody is about 21 days (e.g., is 21 days).

130. The method of paragraph 129, wherein the method comprises administering to the subject the bispecific antibody on or about Day 1 (e.g., Day 1 ±1 day) of each of the one or more dosing cycles.

131 . The method of any one of paragraphs 125-130, wherein the method comprises administering to the subject the bispecific antibody intravenously.

132. The method of paragraph 131 , wherein:

(a) the bispecific antibody is administered over 60 (± 15) minutes in a first dosing cycle; and/or

(b) the method comprises one or more additional dosing cycles, and the bispecific antibody is administered over 30 (± 10) minutes in the one or more additional dosing cycles.

133. The method of any one of paragraphs 125-132, wherein the method comprises administering to the subject the nab-paclitaxel at a dose of about 100 mg/m² once a week (e.g., at a dose of 100 mg/m² once a week) for three weeks, followed by 1 week off.

134. The method of any one of paragraphs 125-133, wherein the method comprises administering to the subject the bispecific antibody at a fixed dose of about 600 mg every three weeks (e.g., at a fixed dose of 600 mg every three weeks) and the nab-paclitaxel at a dose of about 100 mg/m² once a week (e.g., at a dose of 100 mg/m² once a week) for three weeks, followed by 1 week off.

135. The method of any one of paragraphs 125-134, wherein the length of each of the one or more dosing cycles of nab-paclitaxel is about 28 days (e.g., is 28 days).

136. The method of paragraph 135, wherein the method comprises administering to the subject the nab- paclitaxel on Days 1 , 8, and 15 of each of the one or more dosing cycles.

137. The method of any one of paragraphs 125-136, wherein the method comprises administering to the subject the nab-paclitaxel intravenously.

138. The method of paragraph 137, wherein the nab-paclitaxel is administered over about 30 minutes (e.g., is administered over 30 minutes). 139. The method of any one of paragraphs 125-138, wherein, on days on which the bispecific antibody and the chemotherapeutic agent (e.g., taxane, e.g., nab-paclitaxel) are administered on the same day, the method comprises administering to the subject the bispecific antibody before the chemotherapeutic agent (e.g., taxane, e.g., nab-paclitaxel).

140. The method of any one of paragraphs 125-139, wherein the cancer is locally advanced, unresectable or metastatic (e.g., the TNBC is a locally advanced, unresectable or metastatic TNBC).

141 . The method of any one of paragraphs 125-140, wherein the subject does not have any symptomatic, untreated, or actively progressing central nervous system (CNS) metastases.

142. The method of any one of paragraphs 125-141 , wherein the cancer is PD-L1 -positive (e.g., the TNBC is a PD-L1 -positive TNBC).

143. The method of paragraph 142, wherein the PD-L1 -positive cancer (e.g., PD-L1 -positive TNBC) has a PD-L1 combined positive score (CPS) of > 10, as measured using the pharmDx 22C3 IHC assay.

144. The method of paragraph 142, wherein the PD-L1 -positive cancer (e.g., PD-L1 -positive TNBC) has a PD-L1 tumor area positivity score (TAP) of > 5%, as measured using the Ventana SP263 IHC assay.

145. The method of paragraph 142, wherein the PD-L1 -positive cancer (e.g., PD-L1 -positive TNBC) has a PD-L1 -positive immune cell (IC) fraction of > 1%, as measured using the Ventana SP142 IHC assay.

146. The method of any one of paragraphs 125-145, wherein the dosing regimen comprises at least 5 or at least 10 dosing cycles of (a) the bispecific antibody and (b) the chemotherapeutic agent, e.g., taxane, e.g., nab-paclitaxel).

147. The method of any one of paragraphs 125-146, wherein the method results in an increase in progression-free survival (PFS) as compared to a reference PFS.

148. The method of paragraph 147, wherein the reference PFS is a PFS of a population of subjects who have received a control therapy.

149. The method of any one of paragraphs 125-148, wherein the method results in an increase in objective response rate (ORR) in a population of subjects treated according to the method as compared to a reference ORR.

150. The method of paragraph 149, wherein the reference ORR is an ORR of a population of subjects who have received a control therapy. 151 . The method of any one of paragraphs 125-150, wherein the method results in an increase in duration of response (DOR) as compared to a reference DOR.

152. The method of paragraph 151 , wherein the reference DOR is a DOR of a population of subjects who have received a control therapy.

153. The method of any one of paragraphs 125-152, wherein the method results in an increase in overall survival (OS) as compared to a reference OS.

154. The method of paragraph 153, wherein the reference OS is an OS of a population of subjects who have received a control therapy.

155. The method of any one of paragraphs 125-154, wherein the method results in an increase in PFS rate at 12 months as compared to a reference PFS rate at 12 months.

156. The method of paragraph 155, wherein the reference PFS rate is a PFS rate of a population of subjects who have received a control therapy.

157. The method of any one of paragraphs 125-156, wherein the method results in an increase in OS rate at 12 months as compared to a reference OS rate at 12 months.

158. The method of paragraph 157, wherein the reference OS rate is a OS rate of a population of subjects who have received a control therapy.

159. The method of any one of paragraphs 148-158, wherein the control therapy comprises pembrolizumab and a chemotherapeutic agent (e.g., a taxane, e.g., nab-paclitaxel) and does not comprise the bispecific antibody.

160. The method of any one of paragraphs 125-159, wherein the bispecific antibody targeting PD-1 and LAG3 comprises a first antigen-binding domain that specifically binds to PD-1 comprising a heavy chain variable (VH) domain comprising:

(i) an HVR-H1 sequence comprising the amino acid sequence of SEQ ID NO: 1 ,

(ii) an HVR-H2 sequence comprising the amino acid sequence GGR, and

(i) an HVR-L1 sequence comprising the amino acid sequence of SEQ ID NO: 3;

(ii) an HVR-L2 sequence comprising the amino acid sequence RSS, and

(iii) an HVR-L3 sequence comprising the amino acid sequence of SEQ ID NO: 4.

161 . The method of paragraph 160, wherein the bispecific antibody targeting PD-1 and LAG3 comprises a Fc domain that is an IgG. 162. The method of paragraph 161 , wherein the IgG Fc domain is an IgG 1 Fc domain or an lgG4 Fc domain.

163. The method of paragraph 161 or 162, wherein the Fc domain comprises one or more amino acid substitutions that reduce binding to an Fc receptor.

164. The method of paragraph 163, wherein the Fc receptor is an Fey receptor.

165. The method of any one of paragraphs 160-164, wherein the bispecific antibody targeting PD-1 and LAG3 comprises a second antigen-binding domain that specifically binds to LAG3 comprising a VH domain comprising:

(i) an HVR-H1 sequence comprising the amino acid sequence of SEQ ID NO: 7,

(i) an HVR-L1 sequence comprising the amino acid sequence of SEQ ID NO: 10,

(ii) an HVR-L2 sequence comprising the amino acid sequence of SEQ ID NO: 1 1 , and (Hi) an HVR-L3 sequence comprising the amino acid sequence of SEQ ID NO: 12.

166. The method of any one of paragraphs 160-165, wherein the first antigen-binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 5 and a VL domain comprising the amino acid sequence of SEQ ID NO: 6, and the second antigen-binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 13 and a VL domain comprising the amino acid sequence of SEQ ID NO: 14.

167. The method of any one of paragraphs 160-166, wherein the bispecific antibody targeting PD-1 and LAG3 comprises:

168. The method of any one of paragraphs 161 -167, wherein the first subunit of the Fc domain comprises the amino acid substitutions S354C and T366W (numbering according to Kabat EU index) and the second subunit of the Fc domain comprises the amino acid substitutions Y349C, T366S, and Y407V (numbering according to Kabat EU index).

169. The method of any one of paragraphs 160-168, wherein the bispecific antibody targeting PD-1 and LAG3 comprises a first Fab fragment comprising said first antigen binding domain specifically binding to PD1 comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 5 and a VL domain comprising the amino acid sequence of SEQ ID NO: 6, and a second Fab fragment comprising the second antigen binding domain specifically binding to LAG3 comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 13 and a VL domain comprising the amino acid sequence of SEQ ID NO: 14, and an Fc domain of human IgG 1 subclass with the amino acid mutations L234A, L235A, and P329G (numbering according to Kabat EU index).

170. The method of paragraph 169, wherein in one of the Fab fragments of the bispecific antibody targeting PD-1 and LAG3 the variable domains VL and VH are replaced by each other so that the VH domain is part of the light chain and the VL domain is part of the heavy chain.

171 . The method of paragraph 170, wherein in the first Fab fragment the variable domains VL and VH are replaced by each other.

172. The method of any one of paragraphs 169-171 , wherein in the constant domain CL of one of the Fab fragments the amino acid at position 124 is substituted independently by lysine (K), arginine (R), or histidine (H) (numbering according to Kabat EU Index), and in the constant domain CH1 the amino acids at positions 147 and 213 are substituted independently by glutamic acid (E) or aspartic acid (D) (numbering according to Kabat EU index).

173. The method of paragraph 172, wherein in the constant domain CL of the second Fab fragment the amino acid at position 124 is substituted independently by lysine (K), arginine (R), or histidine (H) (numbering according to Kabat EU Index), and in the constant domain CH1 the amino acids at positions 147 and 213 are substituted independently by glutamic acid (E) or aspartic acid (D) (numbering according to Kabat EU index).

174. The method of any one of paragraphs 160-173, wherein the bispecific antibody comprises a first heavy chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 15, a first light chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 16, a second heavy chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 17, and a second light chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 18.

175. The method of paragraph 174, wherein the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 15, a first light chain comprising the amino acid sequence of SEQ ID NO: 16, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 17, and a second light chain comprising the amino acid sequence of SEQ ID NO: 18. 176. A method for treating a subject having a locally advanced, unresectable or metastatic cancer (e.g., a locally advanced, unresectable or metastatic TNBC), wherein the method comprises a dosing regimen comprising concurrently administering to the subject:

(1 )

(a) one or more dosing cycles of a bispecific antibody targeting PD-1 and LAG3 comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, wherein the method comprises administering to the subject the bispecific antibody at a fixed dose of 600 mg every three weeks, and wherein the bispecific antibody comprises: a first heavy chain comprising the amino acid sequence of SEQ ID NO: 15, a first light chain comprising the amino acid sequence of SEQ ID NO: 16, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 17, and a second light chain comprising the amino acid sequence of SEQ ID NO: 18; and

(b) one or more dosing cycles of a chemotherapeutic agent (e.g., a taxane, e.g., nab-paclitaxel), wherein, in aspects in which the chemotherapeutic agent is nab-paclitaxel, the method comprises administering to the subject the nab-paclitaxel at a dose of 100 mg/m² once a week for three weeks, followed by 1 week off; or

(2)

(a) one or more dosing cycles of a bispecific antibody targeting PD-1 and LAG3 comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, wherein the method comprises administering to the subject the bispecific antibody at a fixed dose of 600 mg every three weeks, and wherein the bispecific antibody comprises:

(ii) a second antigen-binding domain that specifically binds to LAG3, comprising the following HVRs: an HVR-H1 sequence comprising the amino acid sequence of SEQ ID NO: 7, an HVR-H2 sequence comprising the amino acid sequence of SEQ ID NO: 8, an HVR-H3 sequence comprising an amino acid sequence of SEQ ID NO: 9; an HVR-L1 sequence comprising the amino acid sequence of SEQ ID NO: 10, an HVR-L2 sequence comprising the amino acid sequence of SEQ ID NO: 11 , and an HVR-L3 sequence comprising the amino acid sequence of SEQ ID NO: 12; and

(b) one or more dosing cycles of a chemotherapeutic agent (e.g., a taxane, e.g., nab-paclitaxel), wherein, in aspects in which the chemotherapeutic agent is nab-paclitaxel, the method comprises administering to the subject the nab-paclitaxel at a dose of 100 mg/m² once a week for three weeks, followed by 1 week off. 177. The method of any one of paragraphs 125-176, wherein the subject is a human.

178. A bispecific antibody targeting PD-1 and LAG3 for use in a method of treating a subject having a cancer (e.g., a triple-negative breast cancer (TNBC)), wherein the method comprises a dosing regimen comprising a bispecific antibody targeting PD-1 and LAG3 and a chemotherapeutic agent (e.g., a taxane, e.g., nab-paclitaxel), wherein the bispecific antibody comprises a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, and wherein the dosing regimen comprises concurrently administering to the subject:

(a) one or more dosing cycles of the bispecific antibody; and

(b) one or more dosing cycles of the chemotherapeutic agent (e.g., taxane, e.g., nab-paclitaxel).

179. The bispecific antibody for use of paragraph 178, wherein the subject has not previously received a systemic anti-cancer therapy for locally advanced, unresectable or metastatic cancer (e.g., TNBC).

180. The bispecific antibody for use of paragraph 178 or 179, wherein the subject has not previously been treated with an anti-LAG3 therapy, a CD137 agonist, or an anti-CTLA therapeutic antibody.

181 . The bispecific antibody for use of any one of paragraphs 178-180, wherein the method comprises administering to the subject the bispecific antibody at a fixed dose of about 600 mg (e.g., at a fixed dose of 600 mg) every three weeks.

182. The bispecific antibody for use of any one of paragraphs 178-181 , wherein the length of each of the one or more dosing cycles of the bispecific antibody is about 21 days (e.g., is 21 days).

183. The bispecific antibody for use of paragraph 182, wherein the method comprises administering to the subject the bispecific antibody on or about Day 1 (e.g., Day 1 ±1 day) of each of the one or more dosing cycles.

184. The bispecific antibody for use of any one of paragraphs 178-183, wherein the method comprises administering to the subject the bispecific antibody intravenously.

185. The bispecific antibody for use of paragraph 184, wherein:

(a) the bispecific antibody is to be administered over 60 (± 15) minutes in a first dosing cycle; and/or

(b) the method comprises one or more additional dosing cycles, and the bispecific antibody is to be administered over 30 (± 10) minutes in the one or more additional dosing cycles.

186. The bispecific antibody for use of any one of paragraphs 178-185, wherein the method comprises administering to the subject the nab-paclitaxel at a dose of about 100 mg/m² once a week (e.g., at a dose of 100 mg/m² once a week) week for three weeks, followed by 1 week off. 187. The bispecific antibody for use of any one of paragraphs 178-186, wherein the method comprises administering to the subject the bispecific antibody at a fixed dose about 600 mg every three weeks (e.g., at a fixed dose of 600 mg every three weeks) and the nab-paclitaxel at a dose of about 100 mg/m² once a week (e.g., at a dose of 100 mg/m² once a week) for three weeks, followed by 1 week off.

188. The bispecific antibody for use of any one of paragraphs 178-187, wherein the length of each of the one or more dosing cycles of nab-paclitaxel is about 28 days (e.g., is 28 days).

189. The bispecific antibody for use of paragraph 188, wherein the method comprises administering to the subject the nab-paclitaxel on Days 1 , 8, and 15 of each of the one or more dosing cycles.

190. The bispecific antibody for use of any one of paragraphs 178-189, wherein the method comprises administering to the subject the nab-paclitaxel intravenously.

191 . The bispecific antibody for use of paragraph 190, wherein the nab-paclitaxel is to be administered over about 30 minutes (e.g., is administered over 30 minutes).

192. The bispecific antibody for use of any one of paragraphs 178-191 , wherein, on days on which the bispecific antibody and the chemotherapeutic agent (e.g., taxane, e.g., nab-paclitaxel) are to be administered on the same day, the method comprises administering to the subject the bispecific antibody before the chemotherapeutic agent (e.g., taxane, e.g., nab-paclitaxel).

193. The bispecific antibody for use of any one of paragraphs 178-192, wherein the cancer is locally advanced, unresectable or metastatic (e.g., the TNBC is a locally advanced, unresectable or metastatic TNBC).

194. The bispecific antibody for use of any one of paragraphs 178-193, wherein the subject does not have any symptomatic, untreated, or actively progressing central nervous system (CNS) metastases.

195. The bispecific antibody for use of any one of paragraphs 178-194, wherein the cancer is PD-L1 - positive (e.g., the TNBC is a PD-L1 -positive TNBC).

196. The bispecific antibody for use of paragraph 195, wherein the PD-L1 -positive cancer (e.g., PD-L1 - positive TNBC) has a PD-L1 combined positive score (CPS) of > 10, as measured using the pharmDx 22C3 IHC assay.

197. The bispecific antibody for use of paragraph 195, wherein the PD-L1 -positive cancer (e.g., PD-L1 - positive TNBC) has a PD-L1 tumor area positivity score (TAP) of > 5%, as measured using the Ventana SP263 IHC assay. 198. The bispecific antibody for use of paragraph 195, wherein the PD-L1 -positive cancer (e.g., PD-L1 - positive TNBC) has a PD-L1 -positive immune cell (IC) fraction of > 1%, as measured using the Ventana SP142 IHC assay.

199. The bispecific antibody for use of any one of paragraphs 125-198, wherein the dosing regimen comprises at least 5 or at least 10 dosing cycles of (a) the bispecific antibody and (b) the chemotherapeutic agent, e.g., taxane, e.g., nab-paclitaxel).

200. The bispecific antibody for use of any one of paragraphs 178-199, wherein the method results in an increase in progression-free survival (PFS) as compared to a reference PFS.

201 . The bispecific antibody for use of paragraph 200, wherein the reference PFS is a PFS of a population of subjects who have received a control therapy.

202. The bispecific antibody for use of any one of paragraphs 178-201 , wherein the method results in an increase in objective response rate (ORR) in a population of subjects treated according to the method as compared to a reference ORR.

203. The bispecific antibody for use of paragraph 202, wherein the reference ORR is an ORR of a population of subjects who have received a control therapy.

204. The bispecific antibody for use of any one of paragraphs 178-203, wherein the method results in an increase in duration of response (DOR) as compared to a reference DOR.

205. The bispecific antibody for use of paragraph 204, wherein the reference DOR is a DOR of a population of subjects who have received a control therapy.

206. The bispecific antibody for use of any one of paragraphs 178-205, wherein the method results in an increase in overall survival (OS) as compared to a reference OS.

207. The bispecific antibody for use of paragraph 206, wherein the reference OS is an OS of a population of subjects who have received a control therapy.

208. The bispecific antibody for use of any one of paragraphs 178-207, wherein the method results in an increase in PFS rate at 12 months as compared to a reference PFS rate at 12 months.

209. The bispecific antibody for use of paragraph 208, wherein the reference PFS rate is a PFS rate of a population of subjects who have received a control therapy.

210. The bispecific antibody for use of any one of paragraphs 178-209, wherein the method results in an increase in OS rate at 12 months as compared to a reference OS rate at 12 months. 211 . The bispecific antibody for use of paragraph 210, wherein the reference OS rate is an OS rate of a population of subjects who have received a control therapy.

212. The bispecific antibody for use of any one of paragraphs 201 -211 , wherein the control therapy comprises pembrolizumab and a chemotherapeutic agent (e.g., a taxane, e.g., nab-paclitaxel) and does not comprise the bispecific antibody.

213. The bispecific antibody for use of any one of paragraphs 178-212, wherein the bispecific antibody targeting PD-1 and LAG3 comprises a first antigen-binding domain that specifically binds to PD-1 comprising a heavy chain variable (VH) domain comprising:

(i) an HVR-H1 sequence comprising the amino acid sequence of SEQ ID NO: 1 ,

(ii) an HVR-H2 sequence comprising the amino acid sequence GGR, and

(i) an HVR-L1 sequence comprising the amino acid sequence of SEQ ID NO: 3;

(ii) an HVR-L2 sequence comprising the amino acid sequence RSS, and

(iii) an HVR-L3 sequence comprising the amino acid sequence of SEQ ID NO: 4.

214. The bispecific antibody for use of paragraph 213, wherein the bispecific antibody targeting PD-1 and LAG3 comprises a Fc domain that is an IgG.

215. The bispecific antibody for use of paragraph 214, wherein the IgG Fc domain is an IgG 1 Fc domain or an lgG4 Fc domain.

216. The bispecific antibody for use of paragraph 214 or 215, wherein the Fc domain comprises one or more amino acid substitutions that reduce binding to an Fc receptor.

217. The bispecific antibody for use of paragraph 216, wherein the Fc receptor is an Fey receptor.

218. The bispecific antibody for use of any one of paragraphs 213-217, wherein the bispecific antibody targeting PD-1 and LAG3 comprises a second antigen-binding domain that specifically binds to LAG3 comprising a VH domain comprising:

(i) an HVR-H1 sequence comprising the amino acid sequence of SEQ ID NO: 7,

(ii) an HVR-H2 sequence comprising the amino acid sequence of SEQ ID NO: 8, and

(i) an HVR-L1 sequence comprising the amino acid sequence of SEQ ID NO: 10,

(iii) an HVR-L3 sequence comprising the amino acid sequence of SEQ ID NO: 12. 219. The bispecific antibody for use of any one of paragraphs 213-218, wherein the first antigen-binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 5 and a VL domain comprising the amino acid sequence of SEQ ID NO: 6, and the second antigen-binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 13 and a VL domain comprising the amino acid sequence of SEQ ID NO: 14.

220. The bispecific antibody for use of any one of paragraphs 213-219, wherein the bispecific antibody targeting PD-1 and LAG3 comprises:

221 . The bispecific antibody for use of any one of paragraphs 214-220, wherein the first subunit of the Fc domain comprises the amino acid substitutions S354C and T366W (numbering according to Kabat EU index) and the second subunit of the Fc domain comprises the amino acid substitutions Y349C, T366S, and Y407V (numbering according to Kabat EU index).

222. The bispecific antibody for use of any one of paragraphs 213-221 , wherein the bispecific antibody targeting PD-1 and LAG3 comprises a first Fab fragment comprising said first antigen binding domain specifically binding to PD1 comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 5 and a VL domain comprising the amino acid sequence of SEQ ID NO: 6, and a second Fab fragment comprising the second antigen binding domain specifically binding to LAG3 comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 13 and a VL domain comprising the amino acid sequence of SEQ ID NO: 14, and an Fc domain of human IgG 1 subclass with the amino acid mutations L234A, L235A, and P329G (numbering according to Kabat EU index).

223. The bispecific antibody for use of paragraph 222, wherein in one of the Fab fragments of the bispecific antibody targeting PD-1 and LAG3 the variable domains VL and VH are replaced by each other so that the VH domain is part of the light chain and the VL domain is part of the heavy chain.

224. The bispecific antibody for use of paragraph 223, wherein in the first Fab fragment the variable domains VL and VH are replaced by each other.

225. The bispecific antibody for use of any one of paragraphs 222-224, wherein in the constant domain CL of one of the Fab fragments the amino acid at position 124 is substituted independently by lysine (K), arginine (R), or histidine (H) (numbering according to Kabat EU Index), and in the constant domain CH1 the amino acids at positions 147 and 213 are substituted independently by glutamic acid (E) or aspartic acid (D) (numbering according to Kabat EU index). 226. The bispecific antibody for use of paragraph 225, wherein in the constant domain CL of the second Fab fragment the amino acid at position 124 is substituted independently by lysine (K), arginine (R), or histidine (H) (numbering according to Kabat EU Index), and in the constant domain CH1 the amino acids at positions 147 and 213 are substituted independently by glutamic acid (E) or aspartic acid (D) (numbering according to Kabat EU index).

227. The bispecific antibody for use of any one of paragraphs 213-226, wherein the bispecific antibody comprises a first heavy chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 15, a first light chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 16, a second heavy chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 17, and a second light chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 18.

228. The bispecific antibody for use of paragraph 227, wherein the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 15, a first light chain comprising the amino acid sequence of SEQ ID NO: 16, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 17, and a second light chain comprising the amino acid sequence of SEQ ID NO: 18.

229. A bispecific antibody targeting PD-1 and LAG3 for use in a method of treating a subject having a locally advanced, unresectable or metastatic cancer (e.g., a locally advanced, unresectable or metastatic TNBC), wherein the method comprises a dosing regimen comprising a bispecific antibody targeting PD-1 and LAG3 and nab-paclitaxel, wherein the bispecific antibody targeting PD-1 and LAG3 comprises a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, and wherein the dosing regimen comprises concurrently administering to the subject:

(1 )

(a) one or more dosing cycles of the bispecific antibody at a fixed dose of 600 mg every three weeks, wherein the bispecific antibody comprises: a first heavy chain comprising the amino acid sequence of SEQ ID NO: 15, a first light chain comprising the amino acid sequence of SEQ ID NO: 16, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 17, and a second light chain comprising the amino acid sequence of SEQ ID NO: 18; and

(b) one or more dosing cycles of nab-paclitaxel, wherein the method comprises administering to the subject the nab-paclitaxel at a dose of 100 mg/m² once a week for three weeks, followed by 1 week off; or

(2)

(b) one or more dosing cycles of a chemotherapeutic agent (e.g., a taxane, e.g., nab-paclitaxel), wherein, in aspects in which the chemotherapeutic agent is nab-paclitaxel, the method comprises administering to the subject the nab-paclitaxel at a dose of 100 mg/m² once a week for three weeks, followed by 1 week off.

230. The bispecific antibody for use of any one of paragraphs 178-229, wherein the subject is a human.

Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, the descriptions and examples should not be construed as limiting the scope of the invention.

Claims

WHAT IS CLAIMED IS:

1 . A method for treating a subject having a non-squamous non-small cell lung cancer (NSCLC), the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of:

(a) a bispecific antibody targeting PD-1 and LAG3 comprising a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3;

(b) pemetrexed; and

(c) carboplatin.

2. The method of claim 1 , wherein the method comprises administering to the subject the bispecific antibody at a fixed dose of 600 mg every three weeks.

3. The method of claim 1 or 2, wherein the method comprises administering to the subject the pemetrexed at a dose of 500 mg/m² every three weeks.

4. The method of any one of claims 1 -3, wherein the method comprises administering to the subject the carboplatin at a targeted area under the concentration-time curve (AUC) of 5 mg/mL • min every three weeks.

5. The method of any one of claims 1 -4, wherein the length of each of the one or more dosing cycles is 21 days, and wherein the method comprises administering to the subject the bispecific antibody, the pemetrexed, and the carboplatin on Day 1 of each of the one or more dosing cycles.

6. The method of any one of claims 1 -5, wherein the method comprises (a) administering to the subject the bispecific antibody first, the pemetrexed second, and the carboplatin third, or (b) administering to the subject the pemetrexed first, the carboplatin second, and the bispecific antibody third.

7. The method of any one of claims 1 -6, wherein the method comprises administering to the subject the bispecific antibody, the pemetrexed, and the carboplatin intravenously.

8. The method of claim 7, wherein:

(c) the pemetrexed is administered over 10 minutes; and/or

(d) the carboplatin is administered over 30-60 minutes.

9. The method of any one of claims 1 -8, wherein the dosing regimen comprises four dosing cycles.

10. The method of any one of claims 1 -9, wherein the dosing regimen further comprises one or more additional dosing cycles of (a) the bispecific antibody and (b) pemetrexed.

11 . The method of claim 10, wherein the dosing regimen comprises at least 5 or at least 10 additional dosing cycles of (a) the bispecific antibody and (b) pemetrexed.

12. A method for treating a subject having a squamous NSCLC, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of:

(b) paclitaxel; and

(c) carboplatin.

13. The method of claim 12, wherein the method comprises administering to the subject the bispecific antibody at a fixed dose of 600 mg every three weeks.

14. The method of claim 12 or 13, wherein the method comprises administering to the subject the paclitaxel at a dose of 200 mg/m² every three weeks.

15. The method of any one of claims 12-14, wherein the method comprises administering to the subject the carboplatin at a targeted AUC of 5 mg/mL • min every three weeks.

16. The method of any one of claims 12-15, wherein the length of each of the one or more dosing cycles is 21 days, and wherein the method comprises administering to the subject the bispecific antibody, the paclitaxel, and the carboplatin on Day 1 of each of the one or more dosing cycles.

17. The method of any one of claims 12-16, wherein the method comprises (a) administering to the subject the bispecific antibody first, the paclitaxel second, and the carboplatin third, or (b) administering to the subject the paclitaxel first, the carboplatin second, and the bispecific antibody third.

18. The method of any one of claims 12-17, wherein the method comprises administering to the subject the bispecific antibody, the paclitaxel, and the carboplatin intravenously.

19. The method of claim 18, wherein:

(c) the paclitaxel is administered over 3 hours; and/or

(d) the carboplatin is administered over 30-60 minutes.

20. The method of any one of claims 12-19, wherein the dosing regimen comprises four dosing cycles.

21 . The method of any one of claims 12-20, wherein the dosing regimen further comprises one or more additional dosing cycles of the bispecific antibody.

22. The method of claim 21 , wherein the dosing regimen comprises at least 5 or at least 10 additional dosing cycles of the bispecific antibody.

23. The method of any one of claims 12-22, wherein the subject is premedicated with an oral or IV steroid and antihistamines prior to administration of the paclitaxel.

24. The method of any one of claims 1 -23, wherein the NSCLC is:

(a) a Stage IIIB/IIIC NSCLC; or

(b) a Stage IV NSCLC.

25. The method of any one of claims 1 -24, wherein the subject has not received prior systemic treatment for metastatic NSCLC.

26. The method of any one of claims 1 -25, wherein the subject has not previously been treated with an immune checkpoint blockade therapy.

27. The method of any one of claims 1 -26, wherein the subject has not previously been treated with an anti-cytotoxic T lymphocyte-associated protein 4 (CTLA4) agent, an anti-T cell immunoreceptor with Ig and tyrosine-based inhibition motif domains (TIG IT) agent, an anti-PD-1 therapeutic antibody, an anti-PD-L1 therapeutic antibody, or an anti-LAG3 agent.

28. The method of any one of claims 1 -27, wherein the subject has not previously been treated with a CD137 agonist.

29. The method of any one of claims 1 -28, wherein the subject does not have any symptomatic, untreated, or actively progressing central nervous system (CNS) metastases.

30. The method of any one of claims 1 -29, wherein the subject does not have a known mutation in the epidermal growth factor receptor (EGFR) gene or an anaplastic lymphoma kinase (ALK) fusion oncogene.

31 . The method of any one of claims 1 -30, wherein the subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 .

32. The method of any one of claims 1 -31 , wherein a tumor sample from the NSCLC of the subject has a PD-L1 tumor proportion score (TPS) or a PD-L1 expression level on tumor cells (TCs) of <1%.

33. The method of any one of claims 1 -31 , wherein a tumor sample from the NSCLC of the subject has a PD-L1 TPS or a PD-L1 expression level on TCs of between 1% and 49%.

34. The method of any one of claims 1 -31 , wherein a tumor sample from the NSCLC of the subject has a PD-L1 TPS or a PD-L1 expression level on TCs of >50%.

35. The method of any one of claims 1 -34, wherein the method results in an increase in progression- free survival (PFS) as compared to a reference PFS.

36. The method of claim 35, wherein the reference PFS is a PFS of a population of subjects who have received a control therapy.

37. The method of any one of claims 1 -36, wherein the method results in an increase in objective response rate (ORR) in a population of subjects treated according to the method as compared to a reference ORR.

38. The method of claim 37, wherein the reference ORR is an ORR of a population of subjects who have received a control therapy.

39. The method of any one of claims 1 -38, wherein the method results in an increase in overall survival (OS) as compared to a reference OS.

40. The method of claim 39, wherein the reference OS is an OS of a population of subjects who have received a control therapy.

41 . The method of any one of claims 1 -40, wherein the method results in an increase in duration of response (DOR) as compared to a reference DOR.

42. The method of claim 41 , wherein the reference DOR is a DOR of a population of subjects who have received a control therapy.

43. The method of any one of claims 36-42, wherein:

(a) the subject has a non-squamous NSCLC, and the control therapy comprises pembrolizumab, pemetrexed, and carboplatin and does not comprise the bispecific antibody; or

(b) the subject has a squamous NSCLC, and the control therapy comprises pembrolizumab, paclitaxel, and carboplatin and does not comprise the bispecific antibody.

44. The method of any one of claims 1 -43, wherein the bispecific antibody targeting PD-1 and LAG3 comprises a first antigen-binding domain that specifically binds to PD-1 comprising a heavy chain variable (VH) domain comprising:

(ii) an HVR-H2 sequence comprising the amino acid sequence GGR, and

(i) an HVR-L1 sequence comprising the amino acid sequence of SEQ ID NO: 3;

(ii) an HVR-L2 sequence comprising the amino acid sequence RSS, and

(iii) an HVR-L3 sequence comprising the amino acid sequence of SEQ ID NO: 4.

45. The method of claim 44, wherein the bispecific antibody targeting PD-1 and LAG3 comprises a Fc domain that is an IgG.

46. The method of claim 45, wherein the IgG Fc domain is an IgG 1 Fc domain or an lgG4 Fc domain.

47. The method of claim 45 or 46, wherein the Fc domain comprises one or more amino acid substitutions that reduce binding to an Fc receptor.

48. The method of claim 47, wherein the Fc receptor is an Fey receptor.

49. The method of any one of claims 44-48, wherein the bispecific antibody targeting PD-1 and LAG3 comprises a second antigen-binding domain that specifically binds to LAG3 comprising a VH domain comprising:

(i) an HVR-H1 sequence comprising the amino acid sequence of SEQ ID NO: 7,

(ii) an HVR-H2 sequence comprising the amino acid sequence of SEQ ID NO: 8, and

(i) an HVR-L1 sequence comprising the amino acid sequence of SEQ ID NO: 10,

(iii) an HVR-L3 sequence comprising the amino acid sequence of SEQ ID NO: 12.

50. The method of any one of claims 44-49, wherein the first antigen-binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 5 and a VL domain comprising the amino acid sequence of SEQ ID NO: 6, and the second antigen-binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 13 and a VL domain comprising the amino acid sequence of SEQ ID NO: 14.

51 . The method of any one of claims 44-50, wherein the bispecific antibody targeting PD-1 and LAG3 comprises:

52. The method of any one of claims 45-51 , wherein the first subunit of the Fc domain comprises the amino acid substitutions S354C and T366W (numbering according to Kabat EU index) and the second subunit of the Fc domain comprises the amino acid substitutions Y349C, T366S, and Y407V (numbering according to Kabat EU index).

53. The method of any one of claims 44-52, wherein the bispecific antibody targeting PD-1 and LAG3 comprises a first Fab fragment comprising said first antigen binding domain specifically binding to PD1 comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 5 and a VL domain comprising the amino acid sequence of SEQ ID NO: 6, and a second Fab fragment comprising the second antigen binding domain specifically binding to LAG3 comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 13 and a VL domain comprising the amino acid sequence of SEQ ID NO: 14, and an Fc domain of human IgG 1 subclass with the amino acid mutations L234A, L235A, and P329G (numbering according to Kabat EU index).

54. The method of claim 53, wherein in one of the Fab fragments of the bispecific antibody targeting PD-1 and LAG3 the variable domains VL and VH are replaced by each other so that the VH domain is part of the light chain and the VL domain is part of the heavy chain.

55. The method of claim 54, wherein in the first Fab fragment the variable domains VL and VH are replaced by each other.

56. The method of any one of claims 53-55, wherein in the constant domain CL of one of the Fab fragments the amino acid at position 124 is substituted independently by lysine (K), arginine (R), or histidine (H) (numbering according to Kabat EU Index), and in the constant domain CH1 the amino acids at positions 147 and 213 are substituted independently by glutamic acid (E) or aspartic acid (D) (numbering according to Kabat EU index).

57. The method of claim 56, wherein in the constant domain CL of the second Fab fragment the amino acid at position 124 is substituted independently by lysine (K), arginine (R), or histidine (H) (numbering according to Kabat EU Index), and in the constant domain CH1 the amino acids at positions 147 and 213 are substituted independently by glutamic acid (E) or aspartic acid (D) (numbering according to Kabat EU index).

58. The method of any one of claims 44-57, wherein the bispecific antibody comprises a first heavy chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 15, a first light chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 16, a second heavy chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 17, and a second light chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 18.

59. The method of claim 58, wherein the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 15, a first light chain comprising the amino acid sequence of SEQ ID NO: 16, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 17, and a second light chain comprising the amino acid sequence of SEQ ID NO: 18.

60. A method for treating a subject having a non-squamous Stage IIIB/IIIC NSCLC or a Stage IV NSCLC, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of:

(b) pemetrexed, wherein the method comprises administering to the subject the pemetrexed at a dose of 500 mg/m² every three weeks; and

(c) carboplatin, wherein the method comprises administering to the subject the carboplatin at a targeted area under the concentration-time curve (AUC) of 5 mg/mL • min every three weeks.

61 . A method for treating a subject having a squamous Stage IIIB/IIIC NSCLC or a Stage IV NSCLC, the method comprising administering to the subject a dosing regimen comprising one or more dosing cycles of:

(b) paclitaxel, wherein the method comprises administering to the subject the paclitaxel at a dose of 200 mg/m² every three weeks; and

(c) carboplatin, wherein the method comprises administering to the subject the carboplatin at a targeted AUC of 5 mg/mL • min every three weeks.

62. The method of any one of claims 1 -61 , wherein the subject is a human.

63. A bispecific antibody targeting PD-1 and LAG3 for use in a method of treating a subject having a non-squamous non-small cell lung cancer (NSCLC), wherein the method comprises a dosing regimen comprising a bispecific antibody targeting PD-1 and LAG3, pemetrexed, and carboplatin, wherein the bispecific antibody comprises a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, and wherein the dosing regimen comprises administering to the subject one or more dosing cycles of:

(a) the bispecific antibody;

(b) pemetrexed; and

(c) carboplatin.

64. The bispecific antibody for use of claim 63, wherein the method comprises administering to the subject the bispecific antibody at a fixed dose of 600 mg every three weeks.

65. The bispecific antibody for use of claim 63 or 64, wherein the method comprises administering to the subject the pemetrexed at a dose of 500 mg/m² every three weeks.

66. The bispecific antibody for use of any one of claims 63-65, wherein the method comprises administering to the subject the carboplatin at a targeted area under the concentration-time curve (AUC) of 5 mg/mL • min every three weeks.

67. The bispecific antibody for use of any one of claims 63-66, wherein the length of each of the one or more dosing cycles is 21 days, and wherein the method comprises administering to the subject the bispecific antibody, the pemetrexed, and the carboplatin on Day 1 of each of the one or more dosing cycles.

68. The bispecific antibody for use of any one of claims 63-67, wherein the method comprises (a) administering to the subject the bispecific antibody first, the pemetrexed second, and the carboplatin third, or (b) administering to the subject the pemetrexed first, the carboplatin second, and the bispecific antibody third.

69. The bispecific antibody for use of any one of claims 63-68, wherein the method comprises administering to the subject the bispecific antibody, the pemetrexed, and the carboplatin intravenously.

70. The bispecific antibody for use of claim 69, wherein:

(c) the pemetrexed is to be administered over 10 minutes; and/or

(d) the carboplatin is to be administered over 30-60 minutes.

71 . The bispecific antibody for use of any one of claims 63-70, wherein the dosing regimen comprises four dosing cycles.

72. The bispecific antibody for use of any one of claims 63-71 , wherein the dosing regimen further comprises one or more additional dosing cycles of (a) the bispecific antibody and (b) pemetrexed.

73. The bispecific antibody for use of claim 72, wherein the dosing regimen comprises at least 5 or at least 10 additional dosing cycles of (a) the bispecific antibody and (b) pemetrexed.

74. A bispecific antibody targeting PD-1 and LAG3 for use in a method of treating a subject having a squamous NSCLC, wherein the method comprises a dosing regimen comprising a bispecific antibody targeting PD-1 and LAG3, paclitaxel, and carboplatin, wherein the bispecific antibody comprises a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, and wherein the dosing regimen comprises administering to the subject one or more dosing cycles of:

(a) the bispecific antibody;

(b) paclitaxel; and

(c) carboplatin.

75. The bispecific antibody for use of claim 74, wherein the method comprises administering to the subject the bispecific antibody at a fixed dose of 600 mg every three weeks.

76. The bispecific antibody for use of claim 74 or 75, wherein the method comprises administering to the subject the paclitaxel at a dose of 200 mg/m² every three weeks.

77. The bispecific antibody for use of any one of claims 74-76, wherein the method comprises administering to the subject the carboplatin at a targeted AUC of 5 mg/mL • min every three weeks.

78. The bispecific antibody for use of any one of claims 74-77, wherein the length of each of the one or more dosing cycles is 21 days, and wherein the method comprises administering to the subject the bispecific antibody, the paclitaxel, and the carboplatin on Day 1 of each of the one or more dosing cycles.

79. The bispecific antibody for use of any one of claims 74-78, wherein the method comprises (a) administering to the subject the bispecific antibody first, the paclitaxel second, and the carboplatin third, or (b) administering to the subject the paclitaxel first, the carboplatin second, and the bispecific antibody third.

80. The bispecific antibody for use of any one of claims 74-79, wherein the method comprises administering to the subject the bispecific antibody, the paclitaxel, and the carboplatin intravenously.

81 . The bispecific antibody for use of claim 80, wherein:

(c) the paclitaxel is to be administered over 3 hours; and/or

(d) the carboplatin is to be administered over 30-60 minutes.

82. The bispecific antibody for use of any one of claims 74-80, wherein the dosing regimen comprises four dosing cycles.

83. The bispecific antibody for use of any one of claims 74-82, wherein the dosing regimen further comprises one or more additional dosing cycles of the bispecific antibody.

84. The bispecific antibody for use of claim 83, wherein the dosing regimen comprises at least 5 or at least 10 additional dosing cycles of the bispecific antibody.

85. The bispecific antibody for use of any one of claims 74-84, wherein the subject is to be premedicated with an oral or IV steroid and antihistamines prior to administration of the paclitaxel.

86. The bispecific antibody for use of any one of claims 63-85, wherein the NSCLC is:

(a) a Stage IIIB/IIIC NSCLC; or

(b) a Stage IV NSCLC.

87. The bispecific antibody for use of any one of claims 63-86, wherein the subject has not received prior systemic treatment for metastatic NSCLC.

88. The bispecific antibody for use of any one of claims 63-87, wherein the subject has not previously been treated with an immune checkpoint blockade therapy.

89. The bispecific antibody for use of any one of claims 63-88, wherein the subject has not previously been treated with an anti-cytotoxic T lymphocyte-associated protein 4 (CTLA4) agent, an anti-T cell immunoreceptor with Ig and tyrosine-based inhibition motif domains (TIGIT) agent, an anti-PD-1 therapeutic antibody, an anti-PD-L1 therapeutic antibody, or an anti-LAG3 agent.

90. The bispecific antibody for use of any one of claims 63-89, wherein the subject has not previously been treated with a CD137 agonist.

91 . The bispecific antibody for use of any one of claims 63-90, wherein the subject does not have any symptomatic, untreated, or actively progressing central nervous system (CNS) metastases.

92. The bispecific antibody for use of any one of claims 63-91 , wherein the subject does not have a known mutation in the epidermal growth factor receptor (EGFR) gene or an anaplastic lymphoma kinase (ALK) fusion oncogene.

93. The bispecific antibody for use of any one of claims 63-92, wherein the subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 .

94. The bispecific antibody for use of any one of claims 63-93, wherein a tumor sample from the NSCLC of the subject has a PD-L1 tumor proportion score (TPS) or a PD-L1 expression level on tumor cells (TCs) of <1%.

95. The bispecific antibody for use of any one of claims 63-93, wherein a tumor sample from the NSCLC of the subject has a PD-L1 TPS or a PD-L1 expression level on TCs of between 1% and 49%.

96. The bispecific antibody for use of any one of claims 63-93, wherein a tumor sample from the NSCLC of the subject has a PD-L1 TPS or a PD-L1 expression level on TCs of >50%.

97. The bispecific antibody for use of any one of claims 63-96, wherein the method results in an increase in progression-free survival (PFS) as compared to a reference PFS.

98. The bispecific antibody for use of claim 97, wherein the reference PFS is a PFS of a population of subjects who have received a control therapy.

99. The bispecific antibody for use of any one of claims 63-98, wherein the method results in an increase in objective response rate (ORR) in a population of subjects treated according to the method as compared to a reference ORR.

100. The bispecific antibody for use of claim 99, wherein the reference ORR is an ORR of a population of subjects who have received a control therapy.

101 . The bispecific antibody for use of any one of claims 63-100, wherein the method results in an increase in overall survival (OS) as compared to a reference OS.

102. The bispecific antibody for use of claim 101 , wherein the reference OS is an OS of a population of subjects who have received a control therapy.

103. The bispecific antibody for use of any one of claims 63-102, wherein the method results in an increase in duration of response (DOR) as compared to a reference DOR.

104. The bispecific antibody for use of claim 103, wherein the reference DOR is a DOR of a population of subjects who have received a control therapy.

105. The bispecific antibody for use of any one of claims 98-104, wherein:

106. The bispecific antibody for use of any one of claims 63-105, wherein the bispecific antibody targeting PD-1 and LAG3 comprises a first antigen-binding domain that specifically binds to PD-1 comprising a heavy chain variable (VH) domain comprising:

(ii) an HVR-H2 sequence comprising the amino acid sequence GGR, and

(i) an HVR-L1 sequence comprising the amino acid sequence of SEQ ID NO: 3;

(ii) an HVR-L2 sequence comprising the amino acid sequence RSS, and

(iii) an HVR-L3 sequence comprising the amino acid sequence of SEQ ID NO: 4.

107. The bispecific antibody for use of claim 106, wherein the bispecific antibody targeting PD-1 and LAG3 comprises a Fc domain that is an IgG.

108. The bispecific antibody for use of claim 107, wherein the IgG Fc domain is an IgG 1 Fc domain or an lgG4 Fc domain.

109. The bispecific antibody for use of claim 107 or 108, wherein the Fc domain comprises one or more amino acid substitutions that reduce binding to an Fc receptor.

110. The bispecific antibody for use of claim 109, wherein the Fc receptor is an Fey receptor.

111. The bispecific antibody for use of any one of claims 106-110, wherein the bispecific antibody targeting PD-1 and LAG3 comprises a second antigen-binding domain that specifically binds to LAG3 comprising a VH domain comprising:

(i) an HVR-H1 sequence comprising the amino acid sequence of SEQ ID NO: 7,

(ii) an HVR-H2 sequence comprising the amino acid sequence of SEQ ID NO: 8, and

(i) an HVR-L1 sequence comprising the amino acid sequence of SEQ ID NO: 10,

(iii) an HVR-L3 sequence comprising the amino acid sequence of SEQ ID NO: 12.

1 12. The bispecific antibody for use of any one of claims 106-1 1 1 , wherein the first antigen-binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 5 and a VL domain comprising the amino acid sequence of SEQ ID NO: 6, and the second antigen-binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 13 and a VL domain comprising the amino acid sequence of SEQ ID NO: 14.

1 13. The bispecific antibody for use of any one of claims 106-1 12, wherein the bispecific antibody targeting PD-1 and LAG3 comprises:

1 14. The bispecific antibody for use of any one of claims 107-1 13, wherein the first subunit of the Fc domain comprises the amino acid substitutions S354C and T366W (numbering according to Kabat EU index) and the second subunit of the Fc domain comprises the amino acid substitutions Y349C, T366S, and Y407V (numbering according to Kabat EU index).

1 15. The bispecific antibody for use of any one of claims 106-1 14, wherein the bispecific antibody targeting PD-1 and LAG3 comprises a first Fab fragment comprising said first antigen binding domain specifically binding to PD1 comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 5 and a VL domain comprising the amino acid sequence of SEQ ID NO: 6, and a second Fab fragment comprising the second antigen binding domain specifically binding to LAG3 comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 13 and a VL domain comprising the amino acid sequence of SEQ ID NO: 14, and an Fc domain of human IgG 1 subclass with the amino acid mutations L234A, L235A, and P329G (numbering according to Kabat EU index).

116. The bispecific antibody for use of claim 115, wherein in one of the Fab fragments of the bispecific antibody targeting PD-1 and LAG3 the variable domains VL and VH are replaced by each other so that the VH domain is part of the light chain and the VL domain is part of the heavy chain.

117. The bispecific antibody for use of claim 116, wherein in the first Fab fragment the variable domains VL and VH are replaced by each other.

118. The bispecific antibody for use of any one of claims 115-117, wherein in the constant domain CL of one of the Fab fragments the amino acid at position 124 is substituted independently by lysine (K), arginine (R), or histidine (H) (numbering according to Kabat EU Index), and in the constant domain CH1 the amino acids at positions 147 and 213 are substituted independently by glutamic acid (E) or aspartic acid (D) (numbering according to Kabat EU index).

119. The bispecific antibody for use of claim 118, wherein in the constant domain CL of the second Fab fragment the amino acid at position 124 is substituted independently by lysine (K), arginine (R), or histidine (H) (numbering according to Kabat EU Index), and in the constant domain CH1 the amino acids at positions 147 and 213 are substituted independently by glutamic acid (E) or aspartic acid (D) (numbering according to Kabat EU index).

120. The bispecific antibody for use of any one of claims 106-119, wherein the bispecific antibody comprises a first heavy chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 15, a first light chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 16, a second heavy chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 17, and a second light chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 18.

121 . The bispecific antibody for use of claim 120, wherein the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 15, a first light chain comprising the amino acid sequence of SEQ ID NO: 16, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 17, and a second light chain comprising the amino acid sequence of SEQ ID NO: 18.

122. A bispecific antibody targeting PD-1 and LAG3 for use in a method of treating a subject having a non-squamous Stage IIIB/IIIC NSCLC or a Stage IV NSCLC, wherein the method comprises a dosing regimen comprising a bispecific antibody targeting PD-1 and LAG3, pemetrexed, and carboplatin, wherein the bispecific antibody comprises a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, and wherein the dosing regimen comprises administering to the subject one or more dosing cycles of:

(a) the bispecific antibody, wherein the bispecific antibody comprises: a first heavy chain comprising the amino acid sequence of SEQ ID NO: 15, a first light chain comprising the amino acid sequence of SEQ ID NO: 16, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 17, and a second light chain comprising the amino acid sequence of SEQ ID NO: 18;

123. A bispecific antibody targeting PD-1 and LAG3 for use in a method of treating a subject having a squamous Stage IIIB/IIIC NSCLC or a Stage IV NSCLC, wherein the method comprises a dosing regimen comprising a bispecific antibody targeting PD-1 and LAG3, paclitaxel, and carboplatin, wherein the bispecific antibody comprises a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, and wherein the dosing regimen comprises administering to the subject one or more dosing cycles of:

124. The bispecific antibody for use of any one of claims 63-123, wherein the subject is a human.

125. A method for treating a subject having a triple-negative breast cancer (TNBC), wherein the method comprises a dosing regimen comprising concurrently administering to the subject:

(b) one or more dosing cycles of nab-paclitaxel.

126. The method of claim 125, wherein the subject has not previously received a systemic anticancer therapy for locally advanced, unresectable or metastatic TNBC.

127. The method of claim 125 or 126, wherein the subject has not previously been treated with an anti-LAG3 therapy, a CD137 agonist, or an anti-CTLA therapeutic antibody.

128. The method of any one of claims 125-127, wherein the method comprises administering to the subject the bispecific antibody at a fixed dose of 600 mg every three weeks.

129. The method of any one of claims 125-128, wherein the length of each of the one or more dosing cycles of the bispecific antibody is 21 days.

130. The method of claim 129, wherein the method comprises administering to the subject the bispecific antibody on Day 1 of each of the one or more dosing cycles.

131 . The method of any one of claims 125-130, wherein the method comprises administering to the subject the bispecific antibody intravenously.

132. The method of claim 131 , wherein:

133. The method of any one of claims 125-132, wherein the method comprises administering to the subject the nab-paclitaxel at a dose of 100 mg/m² once a week for three weeks, followed by 1 week off.

134. The method of any one of claims 125-133, wherein the method comprises administering to the subject the bispecific antibody at a fixed dose of 600 mg every three weeks and the nab-paclitaxel at a dose of 100 mg/m² once a week for three weeks, followed by 1 week off.

135. The method of any one of claims 125-134, wherein the length of each of the one or more dosing cycles of nab-paclitaxel is 28 days.

136. The method of claim 135, wherein the method comprises administering to the subject the nab- paclitaxel on Days 1 , 8, and 15 of each of the one or more dosing cycles.

137. The method of any one of claims 125-136, wherein the method comprises administering to the subject the nab-paclitaxel intravenously.

138. The method of claim 137, wherein the nab-paclitaxel is administered over 30 minutes.

139. The method of any one of claims 125-138, wherein, on days on which the bispecific antibody and the nab-paclitaxel are administered on the same day, the method comprises administering to the subject the bispecific antibody before the nab-paclitaxel.

140. The method of any one of claims 125-139, wherein the TNBC is a locally advanced, unresectable or metastatic TNBC.

141 . The method of any one of claims 125-140, wherein the subject does not have any symptomatic, untreated, or actively progressing central nervous system (CNS) metastases.

142. The method of any one of claims 125-141 , wherein the TNBC is a PD-L1 -positive TNBC.

143. The method of claim 142, wherein the PD-L1 -positive TNBC has a PD-L1 combined positive score (CPS) of > 10, as measured using the pharmDx 22C3 IHC assay.

144. The method of claim 142, wherein the PD-L1 -positive TNBC has a PD-L1 tumor area positivity score (TAP) of > 5%, as measured using the Ventana SP263 IHC assay.

145. The method of claim 142, wherein the PD-L1 -positive TNBC has a PD-L1 -positive immune cell (IC) fraction of > 1%, as measured using the Ventana SP142 IHC assay.

146. The method of any one of claims 125-145, wherein the dosing regimen comprises at least 5 or at least 10 dosing cycles of (a) the bispecific antibody and (b) nab-paclitaxel.

147. The method of any one of claims 125-146, wherein the method results in an increase in progression-free survival (PFS) as compared to a reference PFS.

148. The method of claim 147, wherein the reference PFS is a PFS of a population of subjects who have received a control therapy.

149. The method of any one of claims 125-148, wherein the method results in an increase in objective response rate (ORR) in a population of subjects treated according to the method as compared to a reference ORR.

150. The method of claim 149, wherein the reference ORR is an ORR of a population of subjects who have received a control therapy.

151 . The method of any one of claims 125-150, wherein the method results in an increase in duration of response (DOR) as compared to a reference DOR.

152. The method of claim 151 , wherein the reference DOR is a DOR of a population of subjects who have received a control therapy.

153. The method of any one of claims 125-152, wherein the method results in an increase in overall survival (OS) as compared to a reference OS.

154. The method of claim 153, wherein the reference OS is an OS of a population of subjects who have received a control therapy.

155. The method of any one of claims 125-154, wherein the method results in an increase in PFS rate at 12 months as compared to a reference PFS rate at 12 months.

156. The method of claim 155, wherein the reference PFS rate is a PFS rate of a population of subjects who have received a control therapy.

157. The method of any one of claims 125-156, wherein the method results in an increase in OS rate at 12 months as compared to a reference OS rate at 12 months.

158. The method of claim 157, wherein the reference OS rate is a OS rate of a population of subjects who have received a control therapy.

159. The method of any one of claims 148-158, wherein the control therapy comprises pembrolizumab and nab-paclitaxel and does not comprise the bispecific antibody.

160. The method of any one of claims 125-159, wherein the bispecific antibody targeting PD-1 and LAG3 comprises a first antigen-binding domain that specifically binds to PD-1 comprising a heavy chain variable (VH) domain comprising:

(i) an HVR-H1 sequence comprising the amino acid sequence of SEQ ID NO: 1 ,

(ii) an HVR-H2 sequence comprising the amino acid sequence GGR, and

(i) an HVR-L1 sequence comprising the amino acid sequence of SEQ ID NO: 3;

(ii) an HVR-L2 sequence comprising the amino acid sequence RSS, and

(iii) an HVR-L3 sequence comprising the amino acid sequence of SEQ ID NO: 4.

161 . The method of claim 160, wherein the bispecific antibody targeting PD-1 and LAG3 comprises a Fc domain that is an IgG.

162. The method of claim 161 , wherein the IgG Fc domain is an IgG 1 Fc domain or an lgG4 Fc domain.

163. The method of claim 161 or 162, wherein the Fc domain comprises one or more amino acid substitutions that reduce binding to an Fc receptor.

164. The method of claim 163, wherein the Fc receptor is an Fey receptor.

165. The method of any one of claims 160-164, wherein the bispecific antibody targeting PD-1 and LAG3 comprises a second antigen-binding domain that specifically binds to LAG3 comprising a VH domain comprising:

(i) an HVR-H1 sequence comprising the amino acid sequence of SEQ ID NO: 7,

(ii) an HVR-H2 sequence comprising the amino acid sequence of SEQ ID NO: 8, and

(Hi) an HVR-H3 sequence comprising an amino acid sequence of SEQ ID NO: 9; and a VL domain comprising:

(i) an HVR-L1 sequence comprising the amino acid sequence of SEQ ID NO: 10,

(Hi) an HVR-L3 sequence comprising the amino acid sequence of SEQ ID NO: 12.

166. The method of any one of claims 160-165, wherein the first antigen-binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 5 and a VL domain comprising the amino acid sequence of SEQ ID NO: 6, and the second antigen-binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 13 and a VL domain comprising the amino acid sequence of SEQ ID NO: 14.

167. The method of any one of claims 160-166, wherein the bispecific antibody targeting PD-1 and LAG3 comprises:

168. The method of any one of claims 161 -167, wherein the first subunit of the Fc domain comprises the amino acid substitutions S354C and T366W (numbering according to Kabat EU index) and the second subunit of the Fc domain comprises the amino acid substitutions Y349C, T366S, and Y407V (numbering according to Kabat EU index).

169. The method of any one of claims 160-168, wherein the bispecific antibody targeting PD-1 and LAG3 comprises a first Fab fragment comprising said first antigen binding domain specifically binding to PD1 comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 5 and a VL domain comprising the amino acid sequence of SEQ ID NO: 6, and a second Fab fragment comprising the second antigen binding domain specifically binding to LAG3 comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 13 and a VL domain comprising the amino acid sequence of SEQ ID NO: 14, and an Fc domain of human IgG 1 subclass with the amino acid mutations L234A, L235A, and P329G (numbering according to Kabat EU index).

170. The method of claim 169, wherein in one of the Fab fragments of the bispecific antibody targeting PD-1 and LAG3 the variable domains VL and VH are replaced by each other so that the VH domain is part of the light chain and the VL domain is part of the heavy chain.

171 . The method of claim 170, wherein in the first Fab fragment the variable domains VL and VH are replaced by each other.

172. The method of any one of claims 169-171 , wherein in the constant domain CL of one of the Fab fragments the amino acid at position 124 is substituted independently by lysine (K), arginine (R), or histidine (H) (numbering according to Kabat EU Index), and in the constant domain CH1 the amino acids at positions 147 and 213 are substituted independently by glutamic acid (E) or aspartic acid (D) (numbering according to Kabat EU index).

173. The method of claim 172, wherein in the constant domain CL of the second Fab fragment the amino acid at position 124 is substituted independently by lysine (K), arginine (R), or histidine (H) (numbering according to Kabat EU Index), and in the constant domain CH1 the amino acids at positions 147 and 213 are substituted independently by glutamic acid (E) or aspartic acid (D) (numbering according to Kabat EU index).

174. The method of any one of claims 160-173, wherein the bispecific antibody comprises a first heavy chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 15, a first light chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 16, a second heavy chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 17, and a second light chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 18.

175. The method of claim 174, wherein the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 15, a first light chain comprising the amino acid sequence of SEQ ID NO: 16, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 17, and a second light chain comprising the amino acid sequence of SEQ ID NO: 18.

176. A method for treating a subject having a locally advanced, unresectable or metastatic TNBC, wherein the method comprises a dosing regimen comprising concurrently administering to the subject:

(b) one or more dosing cycles of nab-paclitaxel, wherein the method comprises administering to the subject the nab-paclitaxel at a dose of 100 mg/m² once a week for three weeks, followed by 1 week off.

177. The method of any one of claims 125-176, wherein the subject is a human.

178. A bispecific antibody targeting PD-1 and LAG3 for use in a method of treating a subject having a triple-negative breast cancer (TNBC), wherein the method comprises a dosing regimen comprising a bispecific antibody targeting PD-1 and LAG3 and nab-paclitaxel, wherein the bispecific antibody comprises a first antigen-binding domain that specifically binds to PD-1 and a second antigen-binding domain that specifically binds to LAG3, and wherein the dosing regimen comprises concurrently administering to the subject:

(a) one or more dosing cycles of the bispecific antibody; and

(b) one or more dosing cycles of nab-paclitaxel.

179. The bispecific antibody for use of claim 178, wherein the subject has not previously received a systemic anti-cancer therapy for locally advanced, unresectable or metastatic TNBC.

180. The bispecific antibody for use of claim 178 or 179, wherein the subject has not previously been treated with an anti-LAG3 therapy, a CD137 agonist, or an anti-CTLA therapeutic antibody.

181 . The bispecific antibody for use of any one of claims 178-180, wherein the method comprises administering to the subject the bispecific antibody at a fixed dose of 600 mg every three weeks.

182. The bispecific antibody for use of any one of claims 178-181 , wherein the length of each of the one or more dosing cycles of the bispecific antibody is 21 days.

183. The bispecific antibody for use of claim 182, wherein the method comprises administering to the subject the bispecific antibody on Day 1 of each of the one or more dosing cycles.

184. The bispecific antibody for use of any one of claims 178-183, wherein the method comprises administering to the subject the bispecific antibody intravenously.

185. The bispecific antibody for use of claim 184, wherein:

186. The bispecific antibody for use of any one of claims 178-185, wherein the method comprises administering to the subject the nab-paclitaxel at a dose of 100 mg/m² once a week for three weeks, followed by 1 week off.

187. The bispecific antibody for use of any one of claims 178-186, wherein the method comprises administering to the subject the bispecific antibody at a fixed dose of 600 mg every three weeks and the nab-paclitaxel at a dose of 100 mg/m² once a week for three weeks, followed by 1 week off.

188. The bispecific antibody for use of any one of claims 178-187, wherein the length of each of the one or more dosing cycles of nab-paclitaxel is 28 days.

189. The bispecific antibody for use of claim 188, wherein the method comprises administering to the subject the nab-paclitaxel on Days 1 , 8, and 15 of each of the one or more dosing cycles.

190. The bispecific antibody for use of any one of claims 178-189, wherein the method comprises administering to the subject the nab-paclitaxel intravenously.

191 . The bispecific antibody for use of claim 190, wherein the nab-paclitaxel is to be administered over 30 minutes.

192. The bispecific antibody for use of any one of claims 178-191 , wherein, on days on which the bispecific antibody and the nab-paclitaxel are to be administered on the same day, the method comprises administering to the subject the bispecific antibody before the nab-paclitaxel.

193. The bispecific antibody for use of any one of claims 178-192, wherein the TNBC is a locally advanced, unresectable or metastatic TNBC.

194. The bispecific antibody for use of any one of claims 178-193, wherein the subject does not have any symptomatic, untreated, or actively progressing central nervous system (CNS) metastases.

195. The bispecific antibody for use of any one of claims 178-194, wherein the TNBC is a PD-L1 - positive TNBC.

196. The bispecific antibody for use of claim 195, wherein the PD-L1 -positive TNBC has a PD-L1 combined positive score (CPS) of > 10, as measured using the pharmDx 22C3 IHC assay.

197. The bispecific antibody for use of claim 195, wherein the PD-L1 -positive TNBC has a PD-L1 tumor area positivity score (TAP) of > 5%, as measured using the Ventana SP263 IHC assay.

198. The bispecific antibody for use of claim 195, wherein the PD-L1 -positive TNBC has a PD-L1 - positive immune cell (IC) fraction of > 1%, as measured using the Ventana SP142 IHC assay.

199. The bispecific antibody for use of any one of claims 125-198, wherein the dosing regimen comprises at least 5 or at least 10 dosing cycles of (a) the bispecific antibody and (b) nab-paclitaxel.

200. The bispecific antibody for use of any one of claims 178-199, wherein the method results in an increase in progression-free survival (PFS) as compared to a reference PFS.

201 . The bispecific antibody for use of claim 200, wherein the reference PFS is a PFS of a population of subjects who have received a control therapy.

202. The bispecific antibody for use of any one of claims 178-201 , wherein the method results in an increase in objective response rate (ORR) in a population of subjects treated according to the method as compared to a reference ORR.

203. The bispecific antibody for use of claim 202, wherein the reference ORR is an ORR of a population of subjects who have received a control therapy.

204. The bispecific antibody for use of any one of claims 178-203, wherein the method results in an increase in duration of response (DOR) as compared to a reference DOR.

205. The bispecific antibody for use of claim 204, wherein the reference DOR is a DOR of a population of subjects who have received a control therapy.

206. The bispecific antibody for use of any one of claims 178-205, wherein the method results in an increase in overall survival (OS) as compared to a reference OS.

207. The bispecific antibody for use of claim 206, wherein the reference OS is an OS of a population of subjects who have received a control therapy.

208. The bispecific antibody for use of any one of claims 178-207, wherein the method results in an increase in PFS rate at 12 months as compared to a reference PFS rate at 12 months.

209. The bispecific antibody for use of claim 208, wherein the reference PFS rate is a PFS rate of a population of subjects who have received a control therapy.

210. The bispecific antibody for use of any one of claims 178-209, wherein the method results in an increase in OS rate at 12 months as compared to a reference OS rate at 12 months.

211 . The bispecific antibody for use of claim 210, wherein the reference OS rate is an OS rate of a population of subjects who have received a control therapy.

212. The bispecific antibody for use of any one of claims 201 -211 , wherein the control therapy comprises pembrolizumab and nab-paclitaxel and does not comprise the bispecific antibody.

213. The bispecific antibody for use of any one of claims 178-212, wherein the bispecific antibody targeting PD-1 and LAG3 comprises a first antigen-binding domain that specifically binds to PD-1 comprising a heavy chain variable (VH) domain comprising:

(i) an HVR-H1 sequence comprising the amino acid sequence of SEQ ID NO: 1 ,

(ii) an HVR-H2 sequence comprising the amino acid sequence GGR, and

(i) an HVR-L1 sequence comprising the amino acid sequence of SEQ ID NO: 3;

(ii) an HVR-L2 sequence comprising the amino acid sequence RSS, and

(iii) an HVR-L3 sequence comprising the amino acid sequence of SEQ ID NO: 4.

214. The bispecific antibody for use of claim 213, wherein the bispecific antibody targeting PD-1 and LAG3 comprises a Fc domain that is an IgG.

215. The bispecific antibody for use of claim 214, wherein the IgG Fc domain is an lgG1 Fc domain or an lgG4 Fc domain.

216. The bispecific antibody for use of claim 214 or 215, wherein the Fc domain comprises one or more amino acid substitutions that reduce binding to an Fc receptor.

217. The bispecific antibody for use of claim 216, wherein the Fc receptor is an Fey receptor.

218. The bispecific antibody for use of any one of claims 213-217, wherein the bispecific antibody targeting PD-1 and LAG3 comprises a second antigen-binding domain that specifically binds to LAG3 comprising a VH domain comprising:

(i) an HVR-H1 sequence comprising the amino acid sequence of SEQ ID NO: 7,

(ii) an HVR-H2 sequence comprising the amino acid sequence of SEQ ID NO: 8, and

(i) an HVR-L1 sequence comprising the amino acid sequence of SEQ ID NO: 10,

(iii) an HVR-L3 sequence comprising the amino acid sequence of SEQ ID NO: 12.

219. The bispecific antibody for use of any one of claims 213-218, wherein the first antigen-binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 5 and a VL domain comprising the amino acid sequence of SEQ ID NO: 6, and the second antigen-binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 13 and a VL domain comprising the amino acid sequence of SEQ ID NO: 14.

220. The bispecific antibody for use of any one of claims 213-219, wherein the bispecific antibody targeting PD-1 and LAG3 comprises:

221 . The bispecific antibody for use of any one of claims 214-220, wherein the first subunit of the Fc domain comprises the amino acid substitutions S354C and T366W (numbering according to Kabat EU index) and the second subunit of the Fc domain comprises the amino acid substitutions Y349C, T366S, and Y407V (numbering according to Kabat EU index).

222. The bispecific antibody for use of any one of claims 213-221 , wherein the bispecific antibody targeting PD-1 and LAG3 comprises a first Fab fragment comprising said first antigen binding domain specifically binding to PD1 comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 5 and a VL domain comprising the amino acid sequence of SEQ ID NO: 6, and a second Fab fragment comprising the second antigen binding domain specifically binding to LAG3 comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 13 and a VL domain comprising the amino acid sequence of SEQ ID NO: 14, and an Fc domain of human IgG 1 subclass with the amino acid mutations L234A, L235A, and P329G (numbering according to Kabat EU index).

223. The bispecific antibody for use of claim 222, wherein in one of the Fab fragments of the bispecific antibody targeting PD-1 and LAG3 the variable domains VL and VH are replaced by each other so that the VH domain is part of the light chain and the VL domain is part of the heavy chain.

224. The bispecific antibody for use of claim 223, wherein in the first Fab fragment the variable domains VL and VH are replaced by each other.

225. The bispecific antibody for use of any one of claims 222-224, wherein in the constant domain CL of one of the Fab fragments the amino acid at position 124 is substituted independently by lysine (K), arginine (R), or histidine (H) (numbering according to Kabat EU Index), and in the constant domain CH1 the amino acids at positions 147 and 213 are substituted independently by glutamic acid (E) or aspartic acid (D) (numbering according to Kabat EU index).

226. The bispecific antibody for use of claim 225, wherein in the constant domain CL of the second Fab fragment the amino acid at position 124 is substituted independently by lysine (K), arginine (R), or histidine (H) (numbering according to Kabat EU Index), and in the constant domain CH1 the amino acids at positions 147 and 213 are substituted independently by glutamic acid (E) or aspartic acid (D) (numbering according to Kabat EU index).

227. The bispecific antibody for use of any one of claims 213-226, wherein the bispecific antibody comprises a first heavy chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 15, a first light chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 16, a second heavy chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 17, and a second light chain comprising an amino acid sequence with at least 95% sequence identity to the sequence of SEQ ID NO: 18.

228. The bispecific antibody for use of claim 227, wherein the bispecific antibody comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 15, a first light chain comprising the amino acid sequence of SEQ ID NO: 16, a second heavy chain comprising the amino acid sequence of SEQ ID NO: 17, and a second light chain comprising the amino acid sequence of SEQ ID NO: 18.

229. A bispecific antibody targeting PD-1 and LAG3 for use in a method of treating a subject having a locally advanced, unresectable or metastatic TNBC, wherein the method comprises a dosing regimen comprising a bispecific antibody targeting PD-1 and LAG3 and nab-paclitaxel, wherein the bispecific antibody targeting PD-1 and LAG3 comprises a first antigen-binding domain that specifically binds to PD- 1 and a second antigen-binding domain that specifically binds to LAG3, and wherein the dosing regimen comprises concurrently administering to the subject:

230. The bispecific antibody for use of any one of claims 178-229, wherein the subject is a human.