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WO2025185161A1 - Polythérapie comprenant un anticorps bispécifique anti-vegf-a et anti-pd-l1 et une chimiothérapie pour le traitement du cancer - Google Patents

Polythérapie comprenant un anticorps bispécifique anti-vegf-a et anti-pd-l1 et une chimiothérapie pour le traitement du cancer

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Publication number
WO2025185161A1
WO2025185161A1 PCT/CN2024/124994 CN2024124994W WO2025185161A1 WO 2025185161 A1 WO2025185161 A1 WO 2025185161A1 CN 2024124994 W CN2024124994 W CN 2024124994W WO 2025185161 A1 WO2025185161 A1 WO 2025185161A1
Authority
WO
WIPO (PCT)
Prior art keywords
bispecific antibody
antibody
subject
use according
chemotherapy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2024/124994
Other languages
English (en)
Other versions
WO2025185161A8 (fr
Inventor
Guoqiang Hu
Jing Liu
Juan Zhang
Yankui OU
Jie Dong
Ugur Sahin
Na Li
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biotheus Inc
Biontech SE
Original Assignee
Biotheus Inc
Biontech SE
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/CN2024/080506 external-priority patent/WO2025184858A1/fr
Priority claimed from ARP240102655A external-priority patent/AR134001A1/es
Application filed by Biotheus Inc, Biontech SE filed Critical Biotheus Inc
Priority to PCT/CN2025/081278 priority Critical patent/WO2025185733A1/fr
Publication of WO2025185161A1 publication Critical patent/WO2025185161A1/fr
Publication of WO2025185161A8 publication Critical patent/WO2025185161A8/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/22—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against growth factors ; against growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2827—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against B7 molecules, e.g. CD80, CD86
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/569—Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®

Definitions

  • the invention relates to methods for treating cancer in a subject using a bispecific antibody that specifically binds to programmed death-ligand 1 (PD-L1) and Vascular Endothelial Growth Factor (VEGF) in combination with chemotherapy, optionally wherein the subject has a PD-L1 expression score before the treatment, as determined by a combined positive score (CPS) of ⁇ 1 or other integrating scoring algorithm defining a similar PD-L1 expression score.
  • PD-L1 programmed death-ligand 1
  • VEGF Vascular Endothelial Growth Factor
  • the invention further concerns a method for determining whether a cancer in a subject is susceptible to treatment with a bispecific antibody that specifically binds to PD-L1 and VEGF, wherein the method comprises detecting in a sample a PD-L1 expression score before the treatment as determined by a combined positive score (CPS) of ⁇ 1 or other integrating scoring algorithm defining a similar PD-L1 expression score, wherein the CPS of ⁇ 1 indicates that the subject is susceptible to treatment with the bispecific antibody and the chemotherapy.
  • CPS combined positive score
  • ICIs immune checkpoint inhibitors
  • PD-1 programmed cell death protein 1
  • PD-L1 programmed death-ligand 1
  • Predictive biomarkers such as scoring PD-L1 expression in cancer tissue, are therefore used to evaluate the likelihood to respond to ICI treatment alone or in combination with chemotherapy, thereby defining treatment-eligible patient groups (Ulas, Ezgi B et al. “Predictive Value of Combined Positive Score and Tumour Proportion Score for Immunotherapy Response in Advanced NSCLC. ” JTO clinical and research reports vol. 4,9 100532.25 May. 2023, doi: 10.1016/j. jtocrr. 2023.100532) .
  • Cancer types are scored for PD-L1 expression for example by using the combined positive score (CPS) , which covers the PD-L1 expression on both the tumour cells and the immune cells in the tumour microenvironment.
  • CPS combined positive score
  • Studies have explored the relationship between the expression of programmed death ligand 1 (PD-L1) and prognosis in cancer, and high PD-L1 expression determined by immunohistochemistry is suggested to be a predictive biomarker of response to immunotherapy in several cancers (Cortes J, Rugo HS, Cescon DW, et al. Pembrolizumab plus Chemotherapy in Advanced Triple-Negative Breast Cancer. N Engl J Med. 2022; 387 (3) : 217-226.
  • PD-L1 pathway in combination with chemotherapy leads to unsatisfactory responses especially in subjects having a low PD-L1 expression on cancer cells.
  • the approved anti-PD-L1 antibody pembrolizumab plus chemotherapy regime is currently considered the standard of care (SOC) in the first-line treatment of patients with metastatic TNBC whose tumours express PD-L1 with a CPS score of ⁇ 10; and clinically significant improvements have been observed in progression-free survival (PFS) (9.7 months for pembrolizumab plus chemotherapy versus 5.6 months for chemotherapy alone) and overall survival (OS) (23.0 months for pembrolizumab plus chemotherapy versus 16.1 months for chemotherapy alone) .
  • PFS progression-free survival
  • OS overall survival
  • these benefits have not been observed in patients with a CPS of ⁇ 10.
  • the SOC remains chemotherapy alone, with a median PFS of only about6 months and a median OS of about16 months (Cortes et al. 2022) .
  • a chemotherapy preferably a chemotherapy agent
  • the subject has a PD-L1 expression score before the treatment as determined by a combined positive score (CPS) of ⁇ 1 or other integrating scoring algorithm defining a similar PD-L1 expression score.
  • CPS combined positive score
  • the present application provides in an aspect a bispecific antibody that specifically binds to programmed death-ligand 1 (PD-L1) and Vascular Endothelial Growth Factor (VEGF) for use in a method of treating a subject with cancer, the method comprising administering to the subject:
  • PD-L1 programmed death-ligand 1
  • VEGF Vascular Endothelial Growth Factor
  • a chemotherapy preferably a chemotherapy agent.
  • the subject has a PD-L1 expression score before the treatment as determined by a combined positive score (CPS) of ⁇ 1 or other integrating scoring algorithm defining a similar PD-L1 expression score.
  • CPS combined positive score
  • the invention concerns a method of treating cancer in a subject, the method comprising administering to the subject a bispecific antibody that specifically binds to PD-L1 and VEGF in combination with chemotherapy, optionally wherein the subject has a PD-L1 expression score before the treatment as determined by a combined positive score (CPS) of ⁇ 1 or other integrating scoring algorithm defining a similar PD-L1 expression score.
  • CPS combined positive score
  • the present application provides in an aspect a method of treating cancer in a subject, the method comprising administering to the subject a bispecific antibody that specifically binds to PD-L1 and VEGF in combination with chemotherapy. It can be preferred that the subject has a PD-L1 expression score before the treatment as determined by a combined positive score (CPS) of ⁇ 1 or other integrating scoring algorithm defining a similar PD-L1 expression score.
  • CPS combined positive score
  • the invention also concerns a method for determining whether a cancer in a subject is susceptible to treatment with a bispecific antibody that specifically binds to PD-L1 and VEGF and a chemotherapy, wherein the method comprises detecting in a sample of the subject a PD-L1 expression score before the treatment as determined by a combined positive score (CPS) of ⁇ 1 or other integrating scoring algorithm defining a similar PD-L1 expression score, wherein the CPS of ⁇ 1 indicates that the subject is susceptible to treatment with the bispecific antibody and the chemotherapy.
  • CPS combined positive score
  • the invention also concerns a chemotherapy agent for use in a method of treating a subject with cancer, the method comprising administering to the subject:
  • a bispecific antibody that specifically binds to PD-L1 and VEGF
  • the subject has a PD-L1 expression score before the treatment as determined by a combined positive score (CPS) of ⁇ 1 or other integrating scoring algorithm defining a similar PD-L1 expression score.
  • CPS combined positive score
  • a bispecific antibody that specifically binds to PD-L1 and VEGF and a chemotherapy agent in the manufacture of a medicament for treating cancer in a subject, the use comprising administering to the subject:
  • a bispecific antibody that specifically binds to PD-L1 and VEGF in the manufacture of a medicament for treating cancer in a subject, the use comprising administering to the subject:
  • a bispecific antibody that specifically binds to PD-L1 and VEGF and a chemotherapy agent in the manufacture of a medicament for treating cancer in a subject, the use comprising administering to the subject:
  • a chemotherapy agent in the manufacture of a medicament for treating cancer in a subject, the use comprising administering to the subject:
  • a bispecific antibody that specifically binds to PD-L1 and VEGF
  • the invention also provides a kit of parts comprising the bispecific antibody that specifically binds to PD-L1 and VEGF and a chemotherapy agent.
  • a chemotherapy preferably a chemotherapy agent
  • the subject has a PD-L1 expression score before the treatment as determined by a combined positive score (CPS) of ⁇ 1 or other integrating scoring algorithm defining a similar PD-L1 expression score.
  • CPS combined positive score
  • bispecific antibody for use according to embodiment 1, wherein the other integrating scoring algorithms are selected from TAP and TPS.
  • PD-L1 staining cells are tumour cells with partial or complete linear membrane staining that is perceived distinct from cytoplasmic staining, and lymphocytes and macrophages within the tumour nests and/or adjacent supporting stroma with membrane and/or cytoplasmic staining.
  • bispecific antibody for use according to any of the preceding embodiments, wherein the PD-L1 expression is detected by immunohistochemistry (IHC) staining.
  • IHC immunohistochemistry
  • tissue section is a formalin fixed and embedded in paraffin wax (FFPE) tissue section.
  • FFPE paraffin wax
  • H&E hematoxylin and eosin
  • tumour area is determined using a hematoxylin and eosin (H&E) stain.
  • H&E hematoxylin and eosin
  • PD-L1 positive tumour cells and immune cells are PD-L1 staining cells with partial or complete linear membrane staining that is perceived distinct from cytoplasmic staining, and immune cells (lymphocytes and macrophages) within the tumour nests and/or adjacent supporting stroma with membrane and/or cytoplasmic staining.
  • the PD-L1 expression score has been determined using a TPS scoring algorithm by determining in a test sample of the subject the number of tumour cells positive for PD-L1 and the total number of viable tumour cells in a cancer tissue sample from the subject; and calculating the TPS for the cancer tissue sample using the formula:
  • bispecific antibody for use according to any of the preceding embodiments, wherein the bispecific antibody and the chemotherapy are separately administered.
  • bispecific antibody for use according to any of the preceding embodiments, wherein a dosage of the bispecific antibody and a dosage of the chemotherapy are administered concurrently or consecutively.
  • bispecific antibody for use according to any of the preceding embodiments, wherein the bispecific antibody dosage is in a range of from 0.1 mg/kg to 45 mg/kg body weight, preferably 1 mg/kg to 30 mg/kg body weight.
  • bispecific antibody for use according to any of the preceding embodiments, wherein the bispecific antibody and/or the chemotherapy is administered intravenously, preferably wherein the bispecific antibody and the chemotherapy are administered intravenously.
  • bispecific antibody for use according to any of the preceding embodiments, wherein the bispecific antibody and/or the chemotherapy is administered via an IV injection or IV infusion.
  • bispecific antibody for use according to any of the preceding embodiments, wherein a treatment cycle is repeated at least 1, 2, 3, 4, 5, 6, 7, or 8 times.
  • each cycle has up to 28 days, preferably 28 or 21 days.
  • bispecific antibody for use according to any of the preceding embodiments, wherein the bispecific antibody is administered every 6 weeks, preferably every 4 weeks, more preferably every 3 weeks or every 2 weeks.
  • bispecific antibody for use according to any of the preceding embodiments, wherein the bispecific antibody is administered every 2 weeks at a dosage ranging from 10 mg/kg to 30 mg/kg, preferably ranging from 15 mg/kg to 25 mg/kg, more preferably at a dosage of 20 mg/kg.
  • bispecific antibody for use according to any of the preceding embodiments, wherein the bispecific antibody is administered every 3 weeks at a dosage ranging from 20 mg/kg to 40 mg/kg, preferably ranging from 25 mg/kg to 35 mg/kg, more preferably at a dosage of 30 mg/kg.
  • bispecific antibody for use according to any of the preceding embodiments, wherein overall survival is increased in said subject compared to the chemotherapy or the bispecific antibody or an anti-PD-L1 antibody or an anti-PD-1 antibody treatment alone or compared to a standard treatment comprising the chemotherapy and the anti-PD-L1 antibody or the chemotherapy and the anti-PD-1 antibody, wherein the anti-PD-L1 antibody is preferably atezolizumab and the anti-PD-1 antibody is preferably pembrolizumab.
  • bispecific antibody for use according to any of the preceding embodiments, wherein median progression-free survival is increased in said subject compared to the chemotherapy or the bispecific antibody or an anti-PD-L1 antibody or an anti-PD-1 antibody treatment alone or compared to a standard treatment comprising the chemotherapy and the anti-PD-L1 antibody or the chemotherapy and the anti-PD-1 antibody, wherein the anti-PD-L1 antibody is preferably atezolizumab and the anti-PD-1 antibody is preferably pembrolizumab.
  • the cancer is selected from the group consisting of melanoma, lung, liver, stomach, renal cell, urothelial, cervical, colorectal, ovarian, colon, breast, esophagus, mesothelioma, and head and neck cancers, preferably wherein the cancer is selected from urothelial, breast and esophagus cancer.
  • the cancer is small cell lung cancer (SCLC) , non-small cell lung cancer (NSCLC) or triple-negative breast cancer (TNBC) , preferably advanced triple-negative breast cancer.
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • TNBC triple-negative breast cancer
  • bispecific antibody for use according to any of the preceding embodiments, wherein the bispecific antibody comprises an anti-PD-L1 antibody or fragment thereof.
  • bispecific antibody for use according to any of the preceding embodiments, wherein the bispecific antibody comprises an anti-VEGF antibody or fragment thereof.
  • bispecific antibody for use according to any of the preceding embodiments, wherein the bispecific antibody comprises a Fab, Fab’ , F (ab’ ) 2, Fd, Fv, dAb, complementarity determining region fragment, single chain antibody, humanized antibody, chimeric antibody or diabody antibody, preferably a single domain antibody, more preferably a VHH.
  • bispecific antibody for use according to any of the preceding embodiments, wherein the bispecific antibody comprises two anti-PD-L1 single domain antibodies, preferably two VHHs, preferably wherein each VHH is fused to the C-terminus of an anti-VEGF antibody.
  • the bispecific antibody for use according to any of the preceding embodiments, wherein the bispecific antibody comprises an anti-PD-L1 single domain antibody comprising a heavy chain variable region, and the heavy chain variable region comprises: (i) a complementarity-determining region 1 (HCDR1) whose amino acid sequence is shown in SEQ ID NO: 1 or 18, (ii) a complementarity-determining region 2 (HCDR2) whose amino acid sequence is shown in SEQ ID NO: 2 or 19, and (iii) a complementarity-determining region 3 (HCDR3) whose amino acid sequence is shown in SEQ ID NO: 3 or 38.
  • HCDR1 complementarity-determining region 1
  • HCDR2 complementarity-determining region 2
  • HCDR3 complementarity-determining region 3
  • bispecific antibody for use according to any of embodiments 42-47, wherein the anti-VEGF antibody or fragment thereof comprises a IgG1 Fc region, preferably having the amino acid sequence shown in SEQ ID NO: 13 or having at least 95%, 96%, 97%, 98%, or 99%identity to the amino acid sequence shown in SEQ ID NO: 13.
  • bispecific antibody for use according to any of the preceding embodiments, wherein the bispecific antibody specifically binds to VEGF-A.
  • a heavy chain variable region of the anti-VEGF antibody comprises: (i) a complementarity-determining region 1 (HCDR1) whose amino acid sequence is shown in SEQ ID NO: 4, (ii) a complementarity-determining region 2 (HCDR2) whose amino acid sequence is shown in SEQ ID NO: 5, and (iii) a complementarity-determining region 3 (HCDR3) whose amino acid sequence is shown in SEQ ID NO: 6; and
  • a light chain variable region of the anti-VEGF antibody comprises: (i) a complementarity-determining region 1 (LCDR1) whose amino acid sequence is shown in SEQ ID NO: 7, (ii) a complementarity-determining region 2 (LCDR2) whose amino acid sequence is shown in SEQ ID NO: 44, and (iii) a complementarity-determining region 3 (LCDR3) whose amino acid sequence is shown in SEQ ID NO: 8.
  • LCDR1 complementarity-determining region 1
  • LCDR2 complementarity-determining region 2
  • LCDR3 complementarity-determining region 3
  • the bispecific antibody for use according to embodiment 50 wherein the amino acid sequence of the heavy chain variable region of the anti-VEGF antibody is shown in SEQ ID NO: 10, and the amino acid sequence of the light chain variable region of the anti-VEGF antibody is shown in SEQ ID NO: 11; or wherein the amino acid sequence of the heavy chain variable region of the anti-VEGF antibody has at least 95%, 96%, 97%, 98%, or 99%identity to SEQ ID NO: 10, and the amino acid sequence of the light chain variable region of the anti-VEGF antibody has at least 95%, 96%, 97%, 98%, or 99%identity to SEQ ID NO: 11.
  • bispecific antibody for use according to any of the preceding embodiments, wherein the amino acid sequence of the heavy chain of the bispecific antibody is shown in SEQ ID NO: 16, and the amino acid sequence of the light chain variable region of the bispecific antibody is shown in SEQ ID NO: 17; or wherein the amino acid sequence of the heavy chain of the bispecific antibody has at least 95%, 96%, 97%, 98%, or 99%identity to SEQ ID NO: 16, and the amino acid sequence of the light chain variable region of the bispecific antibody has at least 95%, 96%, 97%, 98%, or 99%identity to SEQ ID NO: 17.
  • bispecific antibody for use according to any of embodiments 42-52, wherein the anti-VEGF antibody is bevacizumab.
  • bispecific antibody for use according to any of the preceding embodiments, wherein the bispecific antibody is encoded by one or more nucleic acid molecules.
  • the chemotherapy comprises a chemotherapy agent selected from lurbinectedin, topotecan, taxane such as paclitaxel, docetaxel, or nanoparticle albumin-bound paclitaxel (nab-paclitaxel) , pemetrexed, 5-fluoruracil, irinotecan, etoposide, gemcitabine, anthracyclines, capecitabine, vinorelbine, eribulin, ixabepilone or combinations thereof.
  • a chemotherapy agent selected from lurbinectedin, topotecan, taxane such as paclitaxel, docetaxel, or nanoparticle albumin-bound paclitaxel (nab-paclitaxel) , pemetrexed, 5-fluoruracil, irinotecan, etoposide, gemcitabine, anthracyclines, capecitabine, vinorelbine, eribulin, ixabepilone or combinations thereof.
  • bispecific antibody for use according to any of embodiments 18-55, wherein the platinum-based chemotherapy comprises cisplatin, oxaliplatin or carboplatin.
  • bispecific antibody for use according to any of the preceding embodiments, wherein the method of treatment comprises administering the bispecific antibody in combination with paclitaxel to a subject having small cell lung cancer.
  • bispecific antibody for use according to any of embodiments 1-55, wherein the method of treatment comprises administering the bispecific antibody in combination with pemetrexed and carboplatin (preferably as first line treatment of non-squamous NSCLC) or a taxane (preferably as first line treatment of squamous NSCLC) , such as paclitaxel or docetaxel (preferably as second line treatment of NSCLC) , to a subject having NSCLC, preferably as second line treatment, or wherein the method of treatment comprises administering the bispecific antibody in combination with pemetrexed and carboplatin to a subject having malignant mesothelioma.
  • pemetrexed and carboplatin preferably as first line treatment of non-squamous NSCLC
  • a taxane preferably as first line treatment of squamous NSCLC
  • paclitaxel or docetaxel preferably as second line treatment of NSCLC
  • bispecific antibody for use according to any of embodiments 1-55, wherein the method of treatment comprises administering the bispecific antibody in combination with nab-paclitaxel to a subject having triple-negative breast cancer.
  • bispecific antibody for use according to any of embodiments 1-55, wherein the method of treatment comprises administering the bispecific antibody in combination with irinotecan, 5-fluorouracil, calcium folinate to a subject having unresectable neuroendocrine neoplasm.
  • bispecific antibody for use according to any of embodiments 1-55, wherein the method of treatment comprises administering the bispecific antibody in combination with etoposide and platinum to a subject having small cell lung cancer, preferably as first line treatment and/or extensive-stage small cell lung cancer, most preferably as first line treatment of extensive-stage small cell lung cancer or as second-line treatment of limited-stage small cell lung cancer.
  • the method of treatment comprises administering the bispecific antibody every 3 weeks at a dosage ranging from 20 mg/kg to 30 mg/kg in combination with paclitaxel, lurbinectedin, or topotecan to a subject having small cell lung cancer, preferably as second line treatment and/or extensive-stage small cell lung cancer, more preferably wherein the method of treatment comprises administering to a patient suffering from advanced small cell lung cancer as second line treatment the bispecific antibody every 3 weeks at a dosage of 20 mg/kg or 30 mg/kg in combination with (i) paclitaxel every 3 weeks at a dosage of 175 mg/m 2 , optionally for 5 cycles, or (ii) topotecan at a dosage of 1.5 mg/m 2 administered IV or 2.3 mg/m 2 administered orally once per day on days 1 to 5 of every 3 weeks cycle.
  • bispecific antibody for use according to any of embodiments 1-55, wherein the method of treatment comprises administering the bispecific antibody every 2 weeks at a dosage ranging from 10 mg/kg to 20 mg/kg in combination with nab-paclitaxel, paclitaxel, or gemcitabine with carboplatin to a subject having triple-negative breast cancer.
  • the bispecific antibody for use according to any of embodiments 1-55 wherein the method of treatment comprises administered the bispecific antibody every 2 weeks at a dosage of 1000 mg to 2000 mg to a subject having triple-negative breast cancer, preferably on the 1 st and 15 th day of a 28-day treatment cycle, preferably wherein the bispecific antibody is administered in combination with a chemotherapy, preferably on the 1 st , 8 th , and 15 th day of a 28-day treatment cycle.
  • a method of treating cancer in a subject comprising administering to the subject a bispecific antibody that specifically bind to PD-L1 and VEGF in combination with chemotherapy, optionally wherein the subject has a PD-L1 expression score before the treatment as determined by a combined positive score (CPS) of ⁇ 1, preferably from 1 to 20, preferably from 1 to ⁇ 10, or other integrating scoring algorithm defining a similar PD-L1 expression score.
  • CPS combined positive score
  • the method is a method for extending progression-free survival in said subject compared to the chemotherapy or an anti-PD-L1 antibody or an anti-PD-1 antibody or the bispecific antibody treatment alone or compared to a standard treatment comprising the chemotherapy and the anti-PD-L1 antibody or the chemotherapy and the anti-PD-1 antibody, wherein the anti-PD-L1 antibody is preferably atezolizumab and the anti-PD-1 antibody is preferably pembrolizumab.
  • a method for determining whether a cancer in a subject is susceptible to treatment with a bispecific antibody that specifically binds to PD-L1 and VEGF and a chemotherapy comprises detecting in a sample of the subject a PD-L1 expression score before the treatment as determined by a combined positive score (CPS) of ⁇ 1 or other integrating scoring algorithm defining a similar PD-L1 expression score, wherein the CPS of ⁇ 1 indicates that the subject is susceptible to treatment with the bispecific antibody and the chemotherapy.
  • CPS combined positive score
  • the cancer is selected from the group consisting of melanoma, lung, liver, stomach, renal cell, urothelial, cervical, colorectal, ovarian, colon, breast, esophagus, mesothelioma, and head and neck cancers, preferably wherein the cancer is selected from urothelial, breast and esophagus cancer.
  • bispecific antibody comprises an anti-PD-L1 antibody or fragment thereof.
  • bispecific antibody comprises an anti-VEGF antibody or fragment thereof.
  • bispecific antibody comprises a Fab, Fab', F (ab') 2, Fd, Fv, sdAb, complementarity determining region fragment, single chain antibody, humanized antibody, chimeric antibody or diabody antibody, preferably a single domain antibody, more preferably a VHH.
  • bispecific antibody comprises two anti-PD-L1 single domain antibodies, preferably two VHHs, preferably each VHH is fused to the C-terminus of the anti-VEGF antibody.
  • the bispecific antibody comprises an anti-PD-L1 single domain antibody comprising a heavy chain variable region
  • the heavy chain variable region comprises: (i) a complementarity-determining region 1 (HCDR1) whose amino acid sequence is shown in SEQ ID NO: 1 or 18, (ii) a complementarity-determining region 2 (HCDR2) whose amino acid sequence is shown in SEQ ID NO: 2 or 19, and (iii) a complementarity-determining region 3 (HCDR3) whose amino acid sequence is shown in SEQ ID NO: 3 or 38.
  • the anti-VEGF antibody or fragment thereof comprises a constant region preferably derived from a human antibody, preferably, the constant region is selected from the constant region of human IgGl, IgG2, IgG3 or IgG4.
  • the anti-VEGF antibody or fragment thereof comprises a IgG1 Fc region, preferably having the amino acid sequence shown in SEQ ID NO: 13 or having at least 95%, 96%, 97%, 98%, or 99%identity to the amino acid sequence shown in SEQ ID NO: 13.
  • a heavy chain variable region of the anti-VEGF antibody comprises: (i) a complementarity-determining region 1 (HCDR1) whose amino acid sequence is shown in SEQ ID NO: 4, (ii) a complementarity-determining region 2 (HCDR2) whose amino acid sequence is shown in SEQ ID NO: 5, and (iii) a complementarity-determining region 3 (HCDR3) whose amino acid sequence is shown in SEQ ID NO: 6; and a light chain variable region of the anti-VEGF antibody comprises: (i) a complementarity-determining region 1 (LCDR1) whose amino acid sequence is shown in SEQ ID NO: 7, (ii) a complementarity-determining region 2 (LCDR2) whose amino acid sequence is shown in SEQ ID NO: 44, and (iii) a complementarity-determining region 3 (LCDR3) whose amino acid sequence is shown in SEQ ID NO: 8.
  • the method comprises the step of determining the CPS in a test sample of the subject by determining the number of PD-L1 staining cells (tumour cells, lymphocytes, macrophages) and the total number of viable tumour cells in a cancer tissue sample from the subject; and calculating the CPS for the cancer tissue sample using the formula:
  • PD-L1 staining cells are tumour cells with partial or complete linear membrane staining that is distinct from cytoplasmic staining, and lymphocytes and macrophages within the tumour nests and/or adjacent supporting stroma with membrane and/or cytoplasmic staining.
  • cancer tissue sample is a tissue section of a tumour biopsy.
  • tissue section is a formalin fixed and embedded in paraffin wax (FFPE) tissue section.
  • FFPE paraffin wax
  • the stain comprises a hematoxylin and eosin (H&E) stain.
  • kits of parts comprising a bispecific antibody that specifically binds to PD-L1 and VEGF and a chemotherapy agent.
  • kit of parts according to embodiment 95 or 96 further comprising instructions for use.
  • a chemotherapy agent for use in a method of treating a subject with cancer comprising administering to the subject:
  • a bispecific antibody that specifically binds to PD-L1 and VEGF
  • the subject has a PD-L1 expression score before the treatment as determined by a combined positive score (CPS) of ⁇ 1 or other integrating scoring algorithm defining a similar PD-L1 expression score.
  • CPS combined positive score
  • the chemotherapy agent for use according to embodiment 98, wherein the other integrating scoring algorithms are selected from TAP and TPS.
  • the PD-L1 staining cells are tumour cells with partial or complete linear membrane staining that is perceived distinct from cytoplasmic staining, and lymphocytes and macrophages within the tumour nests and/or adjacent supporting stroma with membrane and/or cytoplasmic staining.
  • tissue section is a formalin fixed and embedded in paraffin wax (FFPE) tissue section.
  • FFPE paraffin wax
  • H&E hematoxylin and eosin
  • tumour area is determined using a hematoxylin and eosin (H&E) stain.
  • H&E hematoxylin and eosin
  • PD-L1 positive tumour cells and immune cells are PD-L1 staining cells with partial or complete linear membrane staining that is perceived distinct from cytoplasmic staining, and immune cells (lymphocytes and macrophages) within the tumour nests and/or adjacent supporting stroma with membrane and/or cytoplasmic staining.
  • the chemotherapy agent for use according to any of embodiments 98-116, wherein the bispecific antibody dosage is in a range of from 0.1 mg/kg to 45 mg/kg body weight, preferably 1 mg/kg to 30 mg/kg body weight.
  • each cycle has up to 28 days, preferably 28 or 21 days.
  • the chemotherapy agent for use according to any of embodiments 98-126 wherein the chemotherapy is administered once or more within the first 20 days or the first 21 days of each cycle, wherein the chemotherapy is administered twice or more within the first 20 days or the first 21 days of each cycle, more preferably wherein the chemotherapy is administered at least thrice within the first 20 days or the first 21 days of each cycle.
  • the chemotherapy agent for use according to any of embodiments 98-129 wherein overall survival is increased in said subject compared to the chemotherapy or the bispecific antibody or an anti-PD-L1 antibody or an anti-PD-1 antibody treatment alone or compared to a standard treatment comprising the chemotherapy and the anti-PD-L1 antibody or the chemotherapy and the anti-PD-1 antibody, wherein the anti-PD-L1 antibody is preferably atezolizumab and the anti-PD-1 antibody is preferably pembrolizumab.
  • the chemotherapy agent for use according to any of embodiments 98-131, wherein the cancer comprises one or more solid tumours.
  • the chemotherapy agent for use according to any of embodiments 98-132 wherein the cancer is selected from the group consisting of melanoma, lung, liver, stomach, renal cell, urothelial, cervical, colorectal, ovarian, colon, breast, esophagus, mesothelioma, and head and neck cancers, preferably wherein the cancer is selected from urothelial, breast and esophagus cancer.
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • TNBC triple-negative breast cancer
  • the bispecific antibody comprises a Fab, Fab’ , F (ab’ ) 2, Fd, Fv, sdAb, complementarity determining region fragment, single chain antibody, humanized antibody, chimeric antibody or diabody antibody, preferably a single domain antibody, more preferably a VHH.
  • the bispecific antibody comprises two anti-PD-L1 single domain antibodies, preferably two VHHs, preferably wherein each VHH is fused to the C-terminus of the anti-VEGF antibody.
  • the bispecific antibody comprises an anti-PD-L1 single domain antibody comprising a heavy chain variable region
  • the heavy chain variable region comprises: (i) a complementarity-determining region 1 (HCDR1) whose amino acid sequence is shown in SEQ ID NO: 1 or 18, (ii) a complementarity-determining region 2 (HCDR2) whose amino acid sequence is shown in SEQ ID NO: 2 or 19, and (iii) a complementarity-determining region 3 (HCDR3) whose amino acid sequence is shown in SEQ ID NO: 3 or 38.
  • the anti-VEGF antibody or fragment thereof comprises a constant region preferably derived from a human antibody, preferably the constant region is selected from the constant region of human IgG1, IgG2, IgG3 or IgG4.
  • a heavy chain variable region of the anti-VEGF antibody comprises: (i) a complementarity-determining region 1 (HCDR1) whose amino acid sequence is shown in SEQ ID NO: 4, (ii) a complementarity-determining region 2 (HCDR2) whose amino acid sequence is shown in SEQ ID NO: 5, and (iii) a complementarity-determining region 3 (HCDR3) whose amino acid sequence is shown in SEQ ID NO: 6; and
  • a light chain variable region of the anti-VEGF antibody comprises: (i) a complementarity-determining region 1 (LCDR1) whose amino acid sequence is shown in SEQ ID NO: 7, (ii) a complementarity-determining region 2 (LCDR2) whose amino acid sequence is shown in SEQ ID NO: 44, and (iii) a complementarity-determining region 3 (LCDR3) whose amino acid sequence is shown in SEQ ID NO: 8.
  • LCDR1 complementarity-determining region 1
  • LCDR2 complementarity-determining region 2
  • LCDR3 complementarity-determining region 3
  • the chemotherapy agent for use according to any of embodiments 115-152, wherein the platinum-based chemotherapy comprises cisplatin, oxaliplatin or carboplatin.
  • the chemotherapy agent for use according to any of embodiments 98-153, wherein the method of treatment comprises administering the bispecific antibody in combination with paclitaxel to a subject having small cell lung cancer.
  • pemetrexed and carboplatin preferably as first line treatment of non-squamous NSCLC
  • a taxane preferably as first line treatment of squamous NSCLC
  • paclitaxel or docetaxel preferably as second line treatment of NSCLC
  • the chemotherapy agent for use according to any of embodiments 98-154, wherein the method of treatment comprises administering the bispecific antibody in combination with nab-paclitaxel to a subject having triple-negative breast cancer.
  • the chemotherapy agent for use according to any of embodiments 98-154, wherein the method of treatment comprises administering the bispecific antibody in combination with irinotecan, 5-fluorouracil, calcium folinate to a subject having unresectable neuroendocrine neoplasm.
  • the chemotherapy agent for use according to any of embodiments 98-154, wherein the method of treatment comprises administering the bispecific antibody in combination with etoposide and platinum to a subject having small cell lung cancer, preferably as first line treatment and/or extensive-stage small cell lung cancer, most preferably as first line treatment of extensive-stage small cell lung cancer or as second-line treatment of limited-stage small cell lung cancer.
  • the method of treatment comprises administering the bispecific antibody every 3 weeks at a dosage ranging from 20 mg/kg to 30 mg/kg in combination with paclitaxel, lurbinectedin, or topotecan to a subject having small cell lung cancer, preferably as second line treatment and/or extensive-stage small cell lung cancer, more preferably wherein the method of treatment comprises administering to a patient suffering from advanced small cell lung cancer as second line treatment the bispecific antibody every 3 weeks at a dosage of 20 mg/kg or 30 mg/kg in combination with (i) paclitaxel every 3 weeks at a dosage of 175 mg/m 2 , optionally for 5 cycles, or (ii) topotecan at a dosage of 1.5 mg/m 2 administered IV or 2.3 mg/m 2 administered orally once per day on days 1 to 5 of every 3 weeks cycle.
  • the chemotherapy agent for use according to any of embodiments 98-154, wherein the method of treatment comprises administering the bispecific antibody every 2 weeks at a dosage ranging from 10 mg/kg to 20 mg/kg in combination with nab-paclitaxel, paclitaxel, or gemcitabine with carboplatin to a subject having triple-negative breast cancer.
  • the chemotherapy agent for use according to any of embodiments 98-154 wherein the method of treatment comprises administered the bispecific antibody every 2 weeks at a dosage of 1000 mg to 2000 mg to a subject having triple-negative breast cancer, preferably on the 1 st and 15 th day of a 28-day treatment cycle and preferably wherein the bispecific antibody is administered in combination with a chemotherapy, preferably on the 1 st , 8 th , and 15 th day of a 28-day treatment cycle.
  • adjuvant relates to a compound which prolongs, enhances or accelerates an immune response.
  • adjuvants comprise a heterogeneous group of compounds such as oil emulsions (e.g., Freund’s adjuvants) , mineral compounds (such as alum) , bacterial products (such as Bordetella pertussis toxin) , or immune-stimulating complexes.
  • adjuvants include, without limitation, LPS, GP96, CpG oligodeoxynucleotides, growth factors, and cytokines, such as monokines, lymphokines, interleukins, chemokines.
  • the chemokines may be IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, INFa, INF- ⁇ , GM-CSF, LT-a.
  • Further known adjuvants are aluminum hydroxide, Freund’s adjuvant or oil such as ISA51.
  • Suitable adjuvants for use in the present disclosure include lipopeptides, such as Pam3Cys, as well as lipophilic components, such as saponins, trehalose-6, 6-dibehenate (TDB) , monophosphoryl lipid-A (MPL) , monomycoloyl glycerol (MMG) , or glucopyranosyl lipid adjuvant (GLA) .
  • lipopeptides such as Pam3Cys
  • lipophilic components such as saponins, trehalose-6, 6-dibehenate (TDB) , monophosphoryl lipid-A (MPL) , monomycoloyl glycerol (MMG) , or glucopyranosyl lipid adjuvant (GLA) .
  • Antibodies are glycoproteins belonging to the immunoglobulin superfamily.
  • the term "full-length antibody” may refer to an immunoglobulin molecule that binds to a target molecule and contains four peptide chains: two heavy chains and two light chains which are connected to each other through disulfide bonds.
  • An antibody may recognise an antigen via the fragment antigen-binding (Fab) variable region.
  • the fragment crystallizable region (Fc region) is the tail region of an antibody that may allow antibodies to activate the immune system.
  • the hinge region is a stretch of heavy chains linking the Fab and Fc regions.
  • the heavy chain and light chain may each comprise a variable region and one or more constant domains.
  • a heavy chain comprises a variable region (VH) and three constant domains (CH1, CH2, and CH3) and a light chain comprises a variable region (VL) and one constant domain (CL) .
  • VH variable region
  • CH1, CH2, and CH3 constant domains
  • VL variable region
  • CL constant domain
  • examples antibodies include a human antibody, a humanized antibody, a chimeric antibody, a multispecific antibody, a monoclonal antibody, and a polyclonal antibody.
  • antibody fragment may refer to a fragment of an antibody, or a genetically engineered product of one of more fragments of an antibody, which fragment is involved in binding with the target molecule.
  • antibody fragments include an antigen-binding fragment (Fab) , a Fab', a Fab'-SH, a fragment antibody (F (ab’ ) 2) , a variable region (Fv) , a single chain antibody (scFv) , a single-domain antibody (sdAb) , and a camelid antibody (VHH) .
  • Antigen-binding fragment refers to a region of an antibody that binds to antigens and is composed of one constant and one variable region of each of the heavy and the light chain.
  • fragment antibody or “F (ab’ ) 2” refers to a region of an antibody that remains following digestion of the Fc region while leaving intact some of the hinge region.
  • Fab refers to a fragment formed by the reduction of a F (ab') 2 fragment.
  • Fab’ -SH refers to a Fab’ fragment with a free sulfhydryl group.
  • carrier refers to a component which may be natural, synthetic, organic, inorganic in which the active component is combined in order to facilitate, enhance or enable administration of the pharmaceutical composition.
  • a carrier as used herein may be one or more compatible solid or liquid fillers, diluents or encapsulating substances, which are suitable for administration to subject. Suitable carriers include, without limitation, sterile water, Ringer, Ringer lactate, sterile sodium chloride solution, isotonic saline, polyalkylene glycols, hydrogenated naphthalenes and, in particular, biocompatible lactide polymers, lactide/glycolide copolymers or polyoxyethylene/polyoxy-propylene copolymers.
  • the pharmaceutical composition of the present disclosure includes isotonic saline.
  • Pharmaceutically acceptable carriers, excipients or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington’s Pharmaceutical Sciences, Mack Publishing Co. (A. R Gennaro edit. 1985) .
  • Pharmaceutical carriers, excipients or diluents can be selected with regard to the intended route of administration and standard pharmaceutical practice.
  • CDR complementarity determining region (s) in an immunoglobulin variable region.
  • the variable regions of the heavy and light chains each contain three CDRs, designated CDR1, CDR2 and CDR3.
  • CDR1, CDR2 and CDR3 The precise boundaries of these CDRs can be defined according to various numbering systems known in the art (see e.g. Dondelinger, M., et al., 2018. Frontiers in immunology, 9, p. 2278) , such as the Kabat numbering system (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed.
  • IMGT/3Dstructure-DB and IMGT/DomainGapAlign a database and a tool for immunoglobulins or antibodies, T cell receptors, MHC, IgSF and MhcSF [J] . Nucleic acids research, 2009; 38 (suppl_1) : D301-D307) .
  • CDRs defined by each numbering system. Also, the correspondence between different numbering systems is well known to those skilled in the art (for example, see Lefranc et al., Dev. Comparat. Immunol. 27: 55-77, 2003) .
  • chemotherapeutic agent or “chemotherapeutical agent” or “chemotherapy agent” can be used interchangeably herein.
  • a chemotherapeutic agent is a chemical compound useful in the treatment of cancer.
  • Classes of chemotherapeutic agents include, but are not limited to: alkylating agents, antimetabolites, kinase inhibitors, spindle poison plant alkaloids, cytotoxic/antitumour antibiotics, topoisomerase inhibitors, photosensitizers, anti-estrogens and selective estrogen receptor modulators (SERMs) , anti-progesterones, estrogen receptor down-regulators (ERDs) , estrogen receptor antagonists, leutinizing hormone-releasing hormone agonists, anti-androgens, aromatase inhibitors, EGFR inhibitors, VEGF inhibitors, anti-sense oligonucleotides that that inhibit expression of genes implicated in abnormal cell proliferation or tumour growth.
  • Chemotherapeutic agents useful in the treatment methods of the present invention include
  • Chimeric antibody refers to an antibody in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in an antibody derived from a particular species (e.g., human) or belonging to a particular antibody class or subclass, while the remainder of the chain (s) is identical with or homologous to corresponding sequences in an antibody derived from another species (e.g., mouse) or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity.
  • a particular species e.g., human
  • another species e.g., mouse
  • the term “comprising” is used in the context of the present disclosure to indicate that further members may optionally be present in addition to the members of the list introduced by “comprising” . It is, however, contemplated as specific embodiments of the present invention that each time the term “comprising” is used, this shall also encompass the possibility of no further members being present, i.e., for the purpose of this embodiment “comprising” can be understood as having the meaning of “consisting of” .
  • Combination therapy refers to the bispecific antibody disclosed herein that specifically binds to PD-L1 and VEGF in combination with the chemotherapy disclosed herein for use in a method of treating a subject with cancer, optionally wherein the subject has been determined to have a combined positive score (CPS) of ⁇ 1 before the treatment.
  • CPS combined positive score
  • Each component of the combination therapy, i.e., the bispecific antibody and the chemotherapy may be administered separately.
  • the “combined positive score” or “CPS, ” refers to a well-known algorithm for determining a PD-L1 expression score from a tumour sample of a subject (see for example Kulangara, Karina &Hanks, Debra &Waldroup, Stephanie &Peltz, Lindsay &Shah, Supriya &Roach, Charlotte &Juco, Jonathan &Emancipator, Kenneth &Stanforth, Dave. (2017) , Development of the combined positive score (CPS) for the evaluation of PD-L1 in solid tumours with the immunohistochemistry assay PD-L1 IHC 22C3 pharmDx. Journal of Clinical Oncology) .
  • the PD-L1 expression score is determined by taken into account the number of PD-L1 staining cells (i.e., tumour cells, lymphocytes, macrophages) and the total number of viable tumour cells in a cancer tissue sample from the subject; and calculating the CPS for the cancer tissue sample using the formula:
  • test sample is a cancer tissue sample
  • the cancer tissue sample comprises at least 100 viable tumour cells as well as (tumour infiltrating) lymphocytes and macrophages; and/or
  • PD-L1 staining cells are determined by PD-L1 immunohistochemistry staining;
  • viable tumour cells are determined by staining with a viability dye
  • the number of PD-L1 staining cells is the sum of PD-L1 staining tumour cells, PD-L1 staining lymphocytes and PD-L1 staining macrophages.
  • the CPS has been determined in a test sample of the subject by determining the number of PD-L1 staining cells (tumour cells, lymphocytes, macrophages) and the total number of viable tumour cells in a cancer tissue sample from the subject; and calculating the CPS for the cancer tissue sample using the formula:
  • test sample is a cancer tissue sample
  • the cancer tissue sample comprises at least 100 viable tumour cells as well as (tumour infiltrating) lymphocytes and macrophages;
  • PD-L1 staining cells are determined by PD-L1 immunohistochemistry staining
  • viable tumour cells are determined by staining with a viability dye
  • the number of PD-L1 staining cells is the sum of PD-L1 staining tumour cells, PD-L1 staining lymphocytes and PD-L1 staining macrophages.
  • the CPS is approved as companion diagnostic for the treatment of cancer using pembrolizumab.
  • diluent relates to a diluting and/or thinning agent.
  • the term “diluent” includes any one or more of fluid, liquid or solid suspension and/or mixing media. Examples of suitable diluents include ethanol, glycerol, and water.
  • DNA relates to a nucleic acid molecule which is entirely or at least substantially composed of deoxyribonucleotide residues. In preferred embodiments, the DNA contains all or a majority of deoxyribonucleotide residues.
  • deoxyribonucleotide refers to a nucleotide which lacks a hydroxyl group at the 2’ -position of a ⁇ -D-ribofuranosyl group.
  • DNA encompasses without limitation, double stranded DNA, single stranded DNA, isolated DNA such as partially purified DNA, essentially pure DNA, synthetic DNA, recombinantly produced DNA, as well as modified DNA that differs from naturally occurring DNA by the addition, deletion, substitution and/or alteration of one or more nucleotides. Such alterations may refer to addition of non-nucleotide material to internal DNA nucleotides or to the end (s) of DNA. It is also contemplated herein that nucleotides in DNA may be non-standard nucleotides, such as chemically synthesized nucleotides or ribonucleotides. For the present disclosure, these altered DNAs are considered analogs of naturally-occurring DNA.
  • a molecule contains “amajority of deoxyribonucleotide residues” if the content of deoxyribonucleotide residues in the molecule is more than 50% (such as at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) , based on the total number of nucleotide residues in the molecule.
  • DNA may be recombinant DNA and may be obtained by cloning of a nucleic acid, in particular cDNA.
  • the cDNA may be obtained by reverse transcription of RNA.
  • the term “effective amount” refers to an amount of a given substance that is sufficient in quantity to produce a desired effect, including an improvement or remediation of the disease, disorder, or symptoms of the disease or condition.
  • the combination therapy described herein is to be administered to a patient in need therefore in an effective amount.
  • RNA molecule can encode an RNA molecule (e.g., by a transcription process that includes a DNA-dependent RNA polymerase enzyme) .
  • RNA molecule can encode a polypeptide (e.g., by a translation process) .
  • a gene, a cDNA, or a single-stranded RNA encodes a polypeptide if transcription and translation of mRNA corresponding to that gene produces the polypeptide in a cell or other biological system.
  • a coding region of a single-stranded RNA encoding a target polypeptide agent refers to a coding strand, the nucleotide sequence of which is identical to the mRNA sequence of such a target polypeptide agent.
  • a coding region of a single-stranded RNA encoding a target polypeptide agent refers to a non-coding strand of such a target polypeptide agent, which may be used as a template for transcription of a gene or cDNA.
  • the phrase “nucleic acid encoding a peptide or protein” means that the polynucleotide, if present in the appropriate environment, for example within a cell and/or in a cell-free translation system, can direct the assembly of amino acids to produce the peptide or protein via a process of translation.
  • epitopes refers to the part of an antigen that as used herein, refers to an agent that elicits an immune response; and/or (ii) an agent that binds to a T cell receptor (e.g., when presented by an MHC molecule) or to an antibody.
  • epitopes are the discrete, three-dimensional sites on an antigen, which are recognized by the immune system.
  • Epitopes usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and usually have specific three-dimensional structural characteristics, as well as specific charge characteristics. Conformational and non- conformational epitopes are distinguished in that the binding to the former but not the latter is lost in the presence of denaturing solvents.
  • excipient refers to a substance which may be present in a pharmaceutical composition of the present disclosure but is not an active ingredient.
  • excipients include without limitation, carriers, binders, diluents, lubricants, thickeners, surface active agents, preservatives, stabilizers, emulsifiers, buffers, flavoring agents, or colorants.
  • a gene refers to a DNA sequence in a chromosome that codes for a protein.
  • a gene includes coding sequence (i.e., sequence that encodes a particular protein) ; in some embodiments, a gene includes non-coding sequence.
  • a gene may include both coding (e.g., exonic) and non-coding (e.g., intronic) sequences.
  • a gene may include one or more regulatory elements that, for example, may control or impact one or more aspects of gene expression (e.g., cell-type-specific expression, inducible expression, etc. ) .
  • Human antibody refers to an antibody that comprises human immunoglobulin protein sequences only.
  • a human antibody may contain murine carbohydrate chains if produced in a mouse, in a mouse cell, or in a hybridoma derived from a mouse cell.
  • mouse antibody or rat antibody refer to an antibody that comprises only mouse or rat immunoglobulin sequences, respectively.
  • Humanized antibody refers to forms of antibodies that contain sequences from non human (e.g., murine) antibodies as well as human antibodies. Such antibodies contain minimal sequence derived from non-human immunoglobulin.
  • the humanized antibody will comprise substantially all of at least one, and typically two, variable regions , in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin sequence.
  • an immune cell means any cell of hematopoietic lineage involved in regulating an immune response against an antigen (e.g., a bacterial or viral infection or an auto-antigen) .
  • an immune cell is a leukocyte, such as a white blood cell.
  • Immune cells include neutrophils, eosinophils, basophils, lymphocytes, and/or monocytes.
  • Lymphocytes include T lymphocytes and B lymphocytes. Immune cells can also be dendritic cells, natural killer (NK) cells, and/or a mast cell.
  • NK natural killer
  • Mononuclear inflammatory cells as used herein refer to lymphocytes and macrophages.
  • the term "monoclonal antibody” refers to an antibody obtained from a substantially homogeneous population of antibodies. The individual antibodies composing the population may be identical except for possible naturally occurring mutations, which may be present in minor amounts. Monoclonal antibodies are highly specific and target a single antigenic epitope. In contrast, polyclonal antibody preparations typically include a large number of antibodies which are specific for different epitopes.
  • nucleoside relates to compounds which can be thought of as nucleotides without a phosphate group. While a nucleoside is a nucleobase linked to a sugar (e.g., ribose or deoxyribose) , a nucleotide is composed of a nucleoside and one or more phosphate groups. Examples of nucleosides include cytidine, uridine, pseudouridine, adenosine, and guanosine. The five standard nucleosides which usually make up naturally occurring nucleic acids are uridine, adenosine, thymidine, cytidine and guanosine.
  • thymidine is more commonly written as “dT” ( “d” represents “deoxy” ) as it contains a 2’ -deoxyribofuranose moiety rather than the ribofuranose ring found in uridine. This is because thymidine is found in deoxyribonucleic acid (DNA) and not ribonucleic acid (RNA) . Conversely, uridine is found in RNA and not DNA. The remaining three nucleosides may be found in both RNA and DNA.
  • RNA In RNA, they would be represented as A, C and G, whereas in DNA they would be represented as dA, dC and dG.
  • a modified purine (A or G) or pyrimidine (C, T, or U) base moiety is, in some embodiments, modified by one or more alkyl groups, e.g., one or more C 1-4 alkyl groups, e.g., one or more methyl groups.
  • modified purine or pyrimidine base moieties include N 7 -alkyl-guanine, N 6 -alkyl-adenine, 5-alkyl-cytosine, 5-alkyl-uracil, and N (1) -alkyl-uracil, such as N 7 -C 1-4 alkyl-guanine, N 6 -C 1-4 alkyl-adenine, 5-C 1-4 alkyl-cytosine, 5-C 1-4 alkyl-uracil, and N (1) -C 1-4 alkyl-uracil, preferably N 7 -methyl-guanine, N 6 -methyl-adenine, 5-methyl-cytosine, 5-methyl-uracil, and N (1) -methyl-uracil.
  • PD-L1 expression score as used herein can be determined using a PD-L1 scoring algorithm such as CPS, TPS, or TAP. As known to the skilled person, the same PD-L1 expression can lead to different numerical values depending on the PD-L1 scoring algorithm.
  • composition relates to a composition comprising a therapeutically effective agent, preferably together with pharmaceutically acceptable carriers, diluents and/or excipients. Said pharmaceutical composition is useful for treating, preventing, or reducing the severity of a disease by administration of said pharmaceutical composition to a subject.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” means solvents, dispersion media, coatings, antibacterial agents and antifungal agents, isotonic agents, and absorption delaying agents, and the like, that are compatible with pharmaceutical administration.
  • pharmaceutically acceptable carrier or excipient is not naturally occurring.
  • Platinum-containing chemotherapy refers to the use of chemotherapeutic agent (s) used to treat cancer that are coordination complexes of platinum. Platinum-containing chemotherapeutic agents are alkylating agents that crosslink DNA, resulting in ineffective DNA mismatch repair and generally leading to apoptosis. Examples of platins include cisplatin, carboplatin, and oxaliplatin.
  • polynucleotide and “nucleic acid” can be used interchangeably herein to refer to polymers of nucleotides.
  • polynucleotide comprises deoxyribonucleic acid (DNA) , ribonucleic acid (RNA) , combinations thereof, and modified forms thereof.
  • the term comprises genomic DNA, cDNA, mRNA, recombinantly produced and chemically synthesized molecules.
  • a polynucleotide is DNA.
  • a polynucleotide is RNA.
  • a polynucleotide is a mixture of DNA and RNA.
  • a polynucleotide may be present as a single-stranded or double-stranded and linear or covalently circularly closed molecule.
  • a polynucleotide can be isolated.
  • isolated polynucleotide means, according to the present disclosure, that the polynucleotide (i) was amplified in vitro, for example via polymerase chain reaction (PCR) for DNA or in vitro transcription (using, e.g., an RNA polymerase) for RNA, (ii) was produced recombinantly by cloning, (iii) was purified, for example, by cleavage and separation by gel electrophoresis, or (iv) was synthesized, for example, by chemical synthesis.
  • PCR polymerase chain reaction
  • RNA polymerase RNA polymerase
  • polypeptide ” “peptide, ” and “protein” are used interchangeably herein to refer to polymers of amino acids.
  • Kabat (1991) Sequences of Proteins of Immunological Interest, 5 th Ed.Public Health Service, National Institutes of Health, Bethesda, Md. ) or Kabat et al., 1992, Sequences of Proteins of Immunological Interest, DIANE Publishing: 2719.
  • recombinant when used in the context of a polynucleotide means a polynucleotide having nucleotide sequences that are not naturally joined together and can be made by artificially combining two otherwise separated segments of sequence. This artificial combination is often accomplished by chemical synthesis or, more commonly, by the artificial manipulation of isolated segments of nucleic acids, for example, by genetic engineering techniques.
  • Recombinant polynucleotides include vectors comprising an amplified or assembled polynucleotide, which can be used to transform or transfect a suitable host cell.
  • a host cell that comprises the recombinant polynucleotide is referred to as a “recombinant host cell. ”
  • the polynucleotide is then expressed in the recombinant host cell to produce a “recombinant polypeptide. ”
  • a recombinant polynucleotide can also comprise a non-coding function.
  • a “single domain antibody” is an antibody composed of a single variable region (e.g., heavy chain variable region) composed of antibody fragments.
  • a single domain antibody, domain antibody or nanobody consists of 4 framework regions and 3 complementarity determining regions, the 4 framework regions are respectively FR1-FR4, and the 3 complementarity determining regions are respectively CDR1 -CDR3.
  • the single domain antibody of the present application may have a structure of FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. These antibodies do not require light chain variable regions to bind antigens with high affinity and specificity.
  • framework region refers to those amino acid residues in an antibody variable region other than the CDR residues as defined above.
  • An antibody that “specifically binds to” a specified target protein is an antibody that exhibits preferential binding to that target as compared to other proteins, but this specificity does not require absolute binding specificity.
  • An antibody is considered “specific” for its intended target if its binding is determinative of the presence of the target protein in a sample, e.g., without producing undesired results such as false positives.
  • Antibodies, or binding fragments thereof, useful in the present invention will bind to the target protein with an affinity that is at least two fold greater, preferably at least ten times greater, more preferably at least 20-times greater, and most preferably at least 100-times greater than the affinity with non-target proteins.
  • an antibody is said to bind specifically to a polypeptide comprising a given amino acid sequence, e.g., the amino acid sequence of a mature human PD-L1 molecule, if it binds to polypeptides comprising that sequence but does not bind to proteins lacking that sequence.
  • a “subject” is a human of either gender (amale or a female) .
  • the subject may be of any age.
  • the subject is female.
  • the subject is male.
  • the subject is a subject having cancer, in particular a female subject having cancer and/or a male subject having cancer.
  • TAP refers to the “Tumour Area Positivity” score.
  • the PD-L1 expression score can be determined using a TAP scoring algorithm in a test sample of the subject by determining the percentage of PD-L1 positive tumour cells and immune cells per tumour area in a cancer tissue sample from the subject; and calculating the TAP for the cancer tissue sample using the formula:
  • test sample is a cancer sample
  • tumour area is the area occupied by all viable tumour cells and the tumour-associated stroma containing tumour-associated immune cells;
  • PD-L1 positive tumour cells and immune cells are determined by PD-L1 immunohistochemistry staining (preferably by using the anti-PD-L1 antibody SP263) ; and/or
  • PD-L1 positive tumour cells and immune cells means the area covered by such PD-L1 positive tumour cells and immune cells;
  • %PD-L1 positive tumour cells and immune cells /tumour area means the area of PD-L1 positive tumour cells and immune cells relative to the tumour area expressed as %.
  • the PD-L1 expression score has been determined using a TAP scoring algorithm in a test sample of the subject by determining the percentage of PD-L1 positive tumour cells and immune cells per tumour area in a cancer tissue sample from the subject; and calculating the TAP for the cancer tissue sample using the formula:
  • test sample is a cancer sample
  • tumour area is the area occupied by all viable tumour cells and the tumour-associated stroma containing tumour-associated immune cells (wherein viable tumour cells are determined by staining with a viability dye) ;
  • PD-L1 positive tumour cells and immune cells are determined by PD-L1 immunohistochemistry staining (preferably by using the anti-PD-L1 antibody SP263) ;
  • PD-L1 positive tumour cells and immune cells means the area covered by such PD-L1 positive tumour cells and immune cells;
  • %PD-L1 positive tumour cells and immune cells /tumour area means the area of PD-L1 positive tumour cells and immune cells relative to the tumour area expressed as %.
  • the TAP score might be referred to as total percentage of the tumour area (tumour and any desmoplastic stroma) covered with tumour cells with PD-L1 membranous staining at any intensity and tumour-associated immune cells with any pattern.
  • TPS refers to the “Tumour Proportion Score” .
  • the PD-L1 expression score can be determined using a TPS scoring algorithm by determining in a test sample of the subject the number of viable tumour cells positive for PD-L1 and the total number of viable tumour cells in a cancer tissue sample from the subject; and calculating the TPS for the cancer tissue sample using the formula:
  • test sample is a cancer tissue sample
  • the cancer tissue sample comprises at least 100 viable tumour cells
  • viable tumour cells are determined by staining with a viability dye
  • PD-L1 positive cells are determined by PD-L1 immunohistochemistry staining.
  • the PD-L1 expression score has been determined using a TPS scoring algorithm by determining in a test sample of the subject the number of viable tumour cells positive for PD-L1 and the total number of viable tumour cells in a cancer tissue sample from the subject; and calculating the TPS for the cancer tissue sample using the formula:
  • test sample is a cancer tissue sample
  • the cancer tissue sample comprises at least 100 viable tumour cells
  • viable tumour cells are determined by staining with a viability dye
  • PD-L1 positive cells are determined by PD-L1 immunohistochemistry staining.
  • treating when used in the context of a disease or disease condition means ameliorating, improving or remedying a disease, disorder, or symptom of a disease or condition associated with the disease, or can mean completely or partially stopping, on a molecular level, the biochemical basis of the disease, etc. It describes an act that leads to the elimination, reduction, alleviation, reversal, or prevention or delay of onset or recurrence of any symptom of a disease.
  • TNBC human epidermal growth factor receptor 2
  • ER estrogen receptors
  • PR progesterone receptors
  • Tumor as it applies to a subject diagnosed with, or suspected of having, a cancer refers to a malignant or potentially malignant neoplasm or tissue mass of any size and includes primary tumours and secondary neoplasms.
  • a solid tumour is an abnormal growth or mass of tissue that usually does not contain cysts or liquid areas. Different types of solid tumours are named for the type of cells that form them. Examples of solid tumours are sarcomas, carcinomas, and lymphomas. Leukemias (cancers of the blood) generally do not form solid tumours (National Cancer Institute, Dictionary of Cancer Terms) .
  • variable regions as used herein means the segment of an antibody which contains three CDRs, designated CDR1, CDR2 and CDR3.
  • a “variable region” of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination.
  • the variable region of the heavy chain may be referred to as “VH. ”
  • the variable region of the light chain may be referred to as “VL. ”
  • the variable regions of both the heavy and light chains comprise three hypervariable regions, the CDRs, which are located within relatively conserved framework regions (FR) .
  • the CDRs are usually aligned by the framework regions, enabling binding to a specific epitope.
  • both light and heavy chains variable regions comprise FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • Recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it was individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as” ) , provided herein is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
  • the present invention provides a bispecific antibody that specifically binds to PD-L1 and VEGF for use in a method of treating a subject with cancer, the method comprising administering to the subject:
  • a chemotherapy preferably a chemotherapy agent
  • the subject has a PD-L1 expression score before the treatment as determined by the combined positive score (CPS) of ⁇ 1, preferably 1 to 20, more preferably 1 to ⁇ 10 or other integrating scoring algorithm defining a similar PD-L1 expression score. It can be preferred that the subject has the afore-mentioned PD-L1 expression score before the treatment.
  • CPS combined positive score
  • the present invention provides a bispecific antibody that specifically binds to PD-L1 and VEGF for use in a method of treating a subject with cancer, the method comprising administering to the subject:
  • a chemotherapy preferably a chemotherapy agent
  • the subject has a PD-L1 expression score before the treatment as determined by the combined positive score (CPS) of ⁇ 1, preferably 1 to 20, more preferably 1 to ⁇ 10.
  • CPS combined positive score
  • the present invention provides a bispecific antibody that specifically binds to PD-L1 and VEGF for use in a method of treating a subject with cancer, the method comprising administering to the subject:
  • a chemotherapy preferably a chemotherapy agent
  • the subject has a PD-L1 expression score before the treatment as determined by an integrating scoring algorithm defining a PD-L1 expression score similar or identical to the CPS of ⁇ 1, preferably 1 to 20, more preferably 1 to ⁇ 10.
  • a PD-L1 expression score determined by an integrating scoring algorithm and defining a PD-L1 expression score similar to the CPS means an ⁇ 80%, preferably ⁇ 85%, more preferably ⁇ 90%, most preferably ⁇ 95% average positive agreement (APA) and ⁇ 80%, preferably ⁇ 85%, more preferably ⁇ 90%, most preferably ⁇ 95%average negative agreement (ANA) , and ⁇ 80%, preferably ⁇ 85%, more preferably ⁇ 90%, most preferably ⁇ 95%overall percent agreement (OPA) between and within readers with 95%confidence intervals (Cis) when comparing the scoring algorithm with the CPS.
  • APA average positive agreement
  • ANA ⁇ 95%average negative agreement
  • OPA overall percent agreement
  • the PD-L1 expression score determined by an integrating scoring algorithm and defining a PD-L1 expression score similar to the CPS can mean an ⁇ 85%average positive agreement (APA) and ⁇ 85%average negative agreement (ANA) , and ⁇ 85% overall percent agreement (OPA) between and within readers with ⁇ 95%confidence intervals (Cis) when comparing the scoring algorithm with the CPS.
  • APA ⁇ 85%average positive agreement
  • ANA ⁇ 85%average negative agreement
  • OPA overall percent agreement
  • the PD-L1 expression score determined by an integrating scoring algorithm and defining a PD-L1 expression score similar to the CPS can mean an ⁇ 90%average positive agreement (APA) and ⁇ 90%average negative agreement (ANA) , and ⁇ 90%overall percent agreement (OPA) between and within readers with ⁇ 95%confidence intervals (Cis) when comparing the scoring algorithm with the CPS.
  • APA ⁇ 90%average positive agreement
  • ANA ⁇ 90%average negative agreement
  • OPA ⁇ 90%overall percent agreement
  • the PD-L1 expression score determined by an integrating scoring algorithm and defining a PD-L1 expression score similar to the CPS can mean an ⁇ 95%average positive agreement (APA) and ⁇ 95%average negative agreement (ANA) , and ⁇ 95%overall percent agreement (OPA) between and within readers with ⁇ 95%confidence intervals (Cis) when comparing the scoring algorithm with the CPS.
  • APA ⁇ 95%average positive agreement
  • ANA ⁇ 95%average negative agreement
  • OPA ⁇ 95%overall percent agreement
  • the other integrating scoring algorithms are selected from TAP and TPS. In some preferred embodiments, the other integrating scoring algorithm is TAP.
  • the integrating scoring algorithm defining a similar PD-L1 expression score preferably is a tumour cell integrating scoring algorithm such TPS or a tumour cell and immune cell integrating scoring algorithm such as CPS or TAP.
  • VEGF Vascular endothelial growth factor
  • VPF vascular permeability factor
  • vasculotropin is a highly specific homodimer that promotes the growth of vascular endothelial cells.
  • VEGF family proteins include VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, VEGF-F and placental growth factor (PIGF) , among which VEGF-A is involved in the early formation of blood vessels play an important role.
  • PIGF placental growth factor
  • VEGF vascular endothelial growth factor
  • VEGF is involved in the pathogenesis and progression of many angiogenesis-dependent diseases, including cancer, certain inflammatory diseases, and diabetic retinopathy. Therefore, VEGF is an important target in antitumour drug research.
  • the main receptors of VEGF proteins are VEGFR1, VEGFR2, VEGFR3, NRP1, NRP2 and NRP3.
  • VEGFA can bind to VEGFR1 and VEGFR2, activate endogenous kinase activation, and promote new blood vessels.
  • Blocking the binding of VEGF to the receptor can be applied to the treatment of various cancers, such as breast cancer, colon cancer, lung cancer, colorectal, ovarian cancer, endometrial cancer, mesothelioma, cervical cancer, kidney cancer (Rakesh R. Ramjiawan, Arjan W. Griffioen, and Dan G. Duda, Angiogenesis. 2017 20 (2) : 185–204. ) .
  • VEGF angiogenesis-modulating capabilities
  • VEGF-A is associated with a range of immunosuppressive effects at successive steps in the cancer-immunity cycle, such as diminished antigen presentation, T cell priming, T cell trafficking, and T cell tumour infiltration.
  • the bispecific antibody binding to VEGF can release immunosuppression.
  • an anti-VEGF antibody treatment alone results in increased gene expression associated with Th1 chemokines involved with T-cell trafficking, tumour MHC-I protein expression and infiltration of tumour-specific T-cell clones demonstrating that an anti-VEGF antibody is capable of inducing anti-tumour immune responses.
  • the bispecific antibody may reverse VEGF-A mediated inhibition of monocyte-to-dendritic cell maturation thereby increasing numbers of dendritic cells (DCs) , and reverse VEGF-A mediated inhibition of dendritic cell maturation thereby increasing tumour-antigen presentation.
  • DCs dendritic cells
  • the bispecific antibody may further reverse or reduce VEGF-A mediated enhanced T cell exhaustion, as VEGF-A binding to VEGFR-2 on the surface of CD8+ T cells has been shown in preclinical studies to result in upregulated expression of the immune-checkpoint molecules (and exhaustion markers) PD ⁇ 1, Cytotoxic T Lymphocyte antigen 4 (CTLA ⁇ 4) , and T cell immunoglobulin mucin receptor 3 (TIM3) as well as that of lymphocyte activation gene 3 protein (LAG3) .
  • the bispecific antibody may further reverse or reduce VEGF-A mediated proliferation of Treg cells, and reverse VEGF-A mediated downregulation of adhesion molecules (e.g. ICAM-1, or CD34) to allow for more efficient immune cell infiltration of the tumour.
  • VEGF thus has a major role in the generation of an immunosuppressive tumour microenvironment.
  • blocking the VEGF-A /VEGFR-2 interaction can induce physical changes in the tumour vasculature such as vascular normalization, a process whereby hypoxia is transiently alleviated and the tumour vasculature reverts back to resemble that of a nonmalignant tissue (Jain, R. K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005) ) .
  • PD-L1 Programmed death-ligand 1
  • CD274 is a member of the B7 family and is a ligand of PD-1.
  • PD-L1 is a type I transmembrane protein with a total of 290 amino acids, including an IgV-like domain, an IgC-like domain, a transmembrane hydrophobic domain and an intracellular domain consisting of 30 amino acids.
  • PD-L1 negatively regulates immune responses. Studies have found that PD-L1 is mainly expressed in activated T cells, B cells, macrophages and dendritic cells, etc.
  • PD-L1 is also expressed in other tissues such as thymus, heart, placenta, etc. endothelial cells, as well as various non-lymphoid lineages such as melanoma, lung cancer, liver cancer, gastric cancer, renal cell cancer, urothelial cancer, cervical cancer, colorectal cancer, ovarian cancer, colon cancer, breast cancer, esophageal cancer, head and neck cancer, etc. (Akintunde Akinleye&Zoaib Rasool, Journal of Hematology&Oncology volume 12, Article number: 92 (2019) ) .
  • PD-L1 regulates autoreactive T-and B-cells, and immune tolerance, and plays a role in peripheral tissue T-and B-cell responses. Interfering with the PD-1: PD-L1 interaction reinvigorates exhausted T cells, as PD-1 is a major regulator of T-cell exhaustion. Hence blocking the PD-1: PD-L1 pathway restores T-cell function and improves tumour eradication.
  • the combination therapy disclosed herein comprising the bispecific antibody targeting specifically PD-L1 and VEGF combined with chemotherapy shows particularly encouraging anti-tumour activity even when the subject has a low PD-L1 expression score.
  • This can distinguish it from treatments of the prior art for the same cancer in which only patient groups with higher PD-L1 expression scores could be effectively targeted by immunotherapy.
  • the combination of the PD-L1 and VEGF bispecific antibody of the invention with the chemotherapy is highly effective in cancer treatment, even in subjects having a low PD-L1 expression score as, e.g., determined by the PD-L1 scoring algorithm CPS of ⁇ 1.
  • the combination of the bispecific antibody and chemotherapy shows a good safety profile for cancer subjects.
  • the release in immunosuppression by blocking VEGF and PD-L1 and the consequential influx of immune cells is contemplated to lead to an increased expression in PD-L1 on tumour cells, further enriching for the bispecific antibody in the tumour microenvironment.
  • the bispecific antibody is contemplated to transform PD-L1 low-expressing tumours into more inflamed, immune cell infiltrated “hot tumours” .
  • the combination therapy comprising the bispecific antibody and chemotherapy can be used in a method of treating cancer in a subject as disclosed herein.
  • the bispecific antibody for use in a method of treating” embodiments equally apply to the corresponding method of treatment embodiments.
  • the bispecific antibody and chemotherapy disclosed herein can provide for substantial improvement in a subject’s overall survival (OS) , progression-free survival (PFS) , objective response rate (ORR) , duration of response, and/or disease control rate.
  • OS overall survival
  • PFS progression-free survival
  • ORR objective response rate
  • duration of response and/or disease control rate.
  • PFS the bispecific antibody and chemotherapy disclosed herein can provide for a PFS of at least about 9 months, preferably of at least about 13 months in patients suffering from TNBC (see also example 3 herein) .
  • Objective Response Rate refers to the number (%) of subjects with at least one visit response of Complete Response (CR) or Partial Response (PR) per RECIST 1.1.
  • Duration of Response refers to the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression (i.e., date of PFS event or censoring –date of first response + 1) .
  • Disease Control Rate refers to the rate of best objective response of CR, PR, or stable disease (SD) according to RECIST 1.1.
  • the PD-L1 expression score as described herein is determined by histologically analyzing a tumour sample and applying a scoring algorithm, the scoring algorithm according to the invention is the combined positive score (CPS) or any other scoring algorithm defining a similar PD-L1 expression score as the CPS.
  • CPS is a well-established scoring algorithm which is approved for the treatment of cancer using pembrolizumab in multiple indications.
  • the treatment method comprises the step of applying the scoring algorithm to determine the PD-L1 expression score and thereby whether the subject shall be treated with the combination therapy of the invention.
  • the PD-L1 expression score (e.g., CPS or similar score type) is already known and provided before the start of the method of the invention.
  • the PD-L1 expression score can be determined in form of the CPS in a test sample of the subject by determining the number of PD-L1 staining cells (tumour cells, lymphocytes, macrophages) and the total number of viable tumour cells in a cancer tissue sample from the subject; and calculating the CPS for the cancer tissue sample using the formula:
  • the PD-L1 staining cells are tumour cells with partial or complete linear membrane staining that is perceived distinct from cytoplasmic staining, and lymphocytes and macrophages within the tumour nests and/or adjacent supporting stroma with membrane and/or cytoplasmic staining.
  • the lymphocytes and macrophages are preferably directly associated with the response against the cancer.
  • the PD-L1 staining cells are tumour cells with convincing partial or complete linear membrane staining (at any intensity) that is perceived distinct from cytoplasmic staining, and lymphocytes and macrophages within the tumour nests and/or adjacent supporting stroma with membrane and/or cytoplasmic staining (at any intensity) .
  • the PD-L1 staining cells are preferably viable PD-L1 staining cells.
  • CPS scoring algorithm is for example described in Kulangara, Karina &Hanks, Debra &Waldroup, Stephanie &Peltz, Lindsay &Shah, Supriya &Roach, Charlotte &Juco, Jonathan &Emancipator, Kenneth &Stanforth, Dave. (2017) , Development of the combined positive score (CPS) for the evaluation of PD-L1 in solid tumours with the immunohistochemistry assay PD-L1 IHC 22C3 pharmDx. Journal of Clinical Oncology, which disclosure is incorporated herein in its entirety.
  • the number of viable tumour cells in the tumour tissue sample are determining by flow cytometry.
  • a tissue sample analyzed by flow cytometry can be contacted with a viability dye prior to analysis, e.g., propidium iodide. Any convenient viability stain may be employed, with many examples known in the art.
  • the tumour proportion score (TPS) (an integrating scoring algorithm) is used instead of the CPS.
  • the TPS can be obtained by determining in a test sample of the subject the number of viable tumour cells positive for PD-L1 (PD-L1 staining tumour cells) and the total number of viable tumour cells in a cancer tissue sample from the subject; and calculating the TPS for the cancer tissue sample using the formula:
  • the number of total tumour cells and tumour cells positive for PD-L1 can be assessed using the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies, Carpinteria, CA, USA) according to the manufacturer’s Instructions for Use.
  • the number of tumour cells can be measured in formalin-fixed tumour samples obtained by core-needle or excisional biopsy of a tumour lesion or from tissue resected at or after the time the cancer was diagnosed.
  • positivity is defined as complete circumferential or partial cell membrane staining of viable tumour cells with 1+ to 3+intensity.
  • Nonspecific staining can be recorded on a 0 to 3 intensity scale, in 0.25 grade increments.
  • Tumour-associated immune cells are preferably excluded from PD-L1 scoring.
  • Cytoplasmic staining, if present, is preferably excluded from the scoring. Scoring can be recorded as percentage of PD-L1-positive tumour cells over total tumour cells in the denominator (TPS) .
  • the TAP scoring algorithm is used as the integrating scoring algorithm instead of CPS.
  • the TAP score can be obtained by determining in a test sample of the subject the number of PD-L1 positive tumour and immune cells (PD-L1 staining tumour and immune cells) and the tumour area in a cancer tissue sample from the subject; and calculating the TAP for the cancer tissue sample using the formula:
  • the TAP score can be determined as described in Liu, Chunyan et al. “Tumour Area Positivity (TAP) score of programmed death-ligand 1 (PD-L1) : a novel visual estimation method for combined tumour cell and immune cell scoring. ” Diagnostic pathology vol. 18, 1 48. 19 Apr. 2023, doi: 10.1186/s13000-023-01318-8, which disclosure is incorporated by reference herein in its entirety.
  • TAP Tuour Area Positivity
  • the tumour area is determined using the hematoxylin and eosin (H&E) stain.
  • the PD-L1 positive tumour cells and immune cells are PD-L1 staining cells with partial or complete linear membrane staining that is distinct from cytoplasmic staining, and immune cells (lymphocytes and macrophages) within the tumour nests and/or adjacent supporting stroma with membrane and/or cytoplasmic staining.
  • tumour area area occupied by all viable tumour cells (TC) and the tumour-associated stroma containing tumour-associated immune cells (IC) ) .
  • the immune cells measured in the nominator are tumour-associated stroma containing tumour-associated immune cells. If tumour nests are separated by non-neoplastic tissue, they can be included as part of the tumour area as long as the tumour nests are bordered on both sides of a 10x field; the intervening non-neoplastic tissue can also be included in the tumour area (commonly abbreviated as 10x field rule) .
  • Tumour-associated IC are preferably intra-and peri-tumoural, including those present within the tumour proper, between tumour nests, and within any tumour-associated reactive stroma. In lymph nodes with focal or discrete tumour metastases, only IC immediately adjacent to the leading edge of the metastatic tumour nest are preferably defined as tumour-associated IC.
  • the TAP can be determined on the IHC slide by visually aggregating/estimating the area covered by PD-L1 positive TC (PD-L1 staining TC) and tumour-associated IC relative to the total tumour area.
  • PD-L1 staining TC PD-L1 staining TC
  • tumour-associated IC PD-L1 positive staining
  • Intra-luminal macrophage staining is preferably not included in the TAP score unless the macrophages completely fill the luminal space and are in direct contact with the TC.
  • Staining of multi-nucleated giant cells, granulomas, and IC located within blood vessels and lymphatics are preferably not included in the TAP.
  • Off-target staining e.g., fibroblasts, endothelial cells, neuroendocrine cells, smooth muscle, and nerves
  • the cancer tissue sample is a tissue section of a tumour biopsy, preferably a solid tumour biopsy.
  • Biopsies of interest can include tumour and/or non-neoplastic biopsies of skin (melanomas, carcinomas, etc. ) , soft tissue, bone, breast, colon, liver, kidney, adrenal, gastrointestinal, pancreatic, gall bladder, salivary gland, cervical, ovary, uterus, testis, prostate, lung, thymus, thyroid, parathyroid, pituitary (adenomas, etc. ) , brain, spinal cord, ocular, nerve, and skeletal muscle, etc.
  • the subject from which the biopsy is obtained has a malignancy is selected from the list consisting of gastric cancer, esophageal carcinomas, head and neck cancer (e.g., head and neck squamous cell carcinoma, or HNSCC) , renal cell carcinoma, urothelial/bladder carcinoma, colorectal cancer, ovarian carcinoma, myeloma, melanoma, lung cancer, classical Hodgkin lymphoma, and breast cancer (e.g., triple-negative breast cancer, hormone receptor positive (ER and/or PR) and Her2 positive breast cancer) , small cell lung cancer including extensive stage small cell lung cancer and limited stage small cell lung cancer, salivary gland carcinoma, vulvar carcinoma, thyroid carcinoma, anal canal carcinoma, biliary carcinoma, mesothelioma, cervical carcinoma, and neuroendocrine carcinoma.
  • gastric cancer esophageal carcinomas
  • head and neck cancer e.g., head and neck squamous cell carcinoma, or HNSCC
  • the subject from which the biopsy is obtained has a malignancy selected from melanoma, liver, stomach, renal cell, colorectal, ovarian, colon, breast, esophagus, mesothelioma, and head and neck cancer.
  • the biopsy of interest can include a tumour and optionally non-neoplastic biopsy of any of a melanoma, liver, stomach, renal cell, colorectal, ovarian, colon, breast, esophagus, mesothelioma, and head and neck solid tumour.
  • the biopsy is obtained from a subject having urothelial, breast, or esophageal cancer, most preferably breast cancer such as TNBC.
  • the CPS is calculated from a stained tumour tissue biopsy section (e.g., on a slide) or serial tumour tissue biopsy sections by immunohistochemistry (IHC) staining, in-situ hybridization (ISH; e.g., fluorescence-in-situ-hybridization, or FISH) , histological stain, and a combination thereof.
  • a tumour tissue biopsy section is analyzed by IHC.
  • the percentage of viable PD-L1 positive and negative tumour cells and PD-L1 positive mononuclear inflammatory cells (MIC) is determined within the tumour nests and the adjacent supporting stroma.
  • cells are positive for PD-L1 staining if they display partial or complete membrane staining relative to all viable tumour cells present in the sample.
  • PD-L1 is detected by immunohistochemistry (IHC) staining.
  • the number of viable tumour cells can be determining by flow cytometry. For example, a tissue sample analyzed by flow cytometry can be contacted with a viability dye prior to analysis, e.g., propidium iodide or any convenient viability stain known in the art.
  • ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇
  • the tumour tissue section is formalin fixed and embedded in paraffin wax (FFPE) .
  • FFPE paraffin wax
  • the tissue section has been fixed in a different way, including tissue sections that have been fixed in, e.g., acrolein, glyoxal, osmium tetroxide, carbodiimide, mercuric chloride, zinc salts, picric acid, potassium di chromate, ethanol, methanol, acetone, and/or acetic acid.
  • the PD-L1 scoring algorithm (such as CPS, TPS, or TAP) is calculated from a tumour tissue sample that is not a fixed section on a slide.
  • the CPS is calculated using flow cytometric analysis of a cell suspension from the tumour tissue sample.
  • the tumour tissue cell suspension can be stained with a detectable PD-L1 binding agent (e.g., a fluorescently labeled antibody) and analyzed on a flow cytometer for counting the number of tumour cells and MIC cells (i.e., lymphocytes and macrophages) expressing PD-L1.
  • a detectable PD-L1 binding agent e.g., a fluorescently labeled antibody
  • MIC cells i.e., lymphocytes and macrophages
  • Tumour cells and MIC cells in the sample can be distinguished using any convenient flow cytometric parameter, e.g., forward scatter (FS) , side scatter (SS) , or by the expression of one or more additional markers using corresponding detectable binding agents for the one or more additional markers, e.g., markers specific or MIC or tumour cells.
  • the cells in the tumour tissue sample can be analyzed on a cell-by-cell basis for mRNA expression of PD-L1 and any other desired target, e.g., using single-cell nucleic acid sequencing methods for gene expression profiling (e.g., next generation sequencing methods) .
  • the tissue section is stained.
  • the stain comprises a hematoxylin and eosin (H&E) stain.
  • Hematoxylin a basic dye, stains nuclei blue due to an affinity to nucleic acids in the cell nucleus; eosin, an acidic dye, stains the cytoplasm pink.
  • a hematoxylin and eosin (H&E) stained section can be used for the evaluation of an acceptable tumour tissue sample or of a tumour area.
  • the staining of a target (e.g., PD-L1) in cells from a tumour tissue biopsy is generally done by contacting the cells with one or more detectable target-specific binding agents under suitable conditions to allow for binding of the target-specific binding agent to its desired target (while minimizing nontarget binding) .
  • a target e.g., PD-L1
  • target-specific binding agent means any agent that specifically binds to a target or analyte of interest, e.g., a target of interest that is present in a tissue section as described herein (e.g., a polypeptide or polynucleotide) .
  • the target-specific binding agent is an antibody (or target-binding fragments thereof) , e.g., as used in IHC and flow cytometry.
  • Staining may be performed with primary and secondary antibodies or without using secondary antibodies (e.g., where the primary antibody is detectably labeled) .
  • Non-limiting examples of anti-PD-L1 antibodies include, but are not limited to, clone 22C3 (Merck &Co. ) , clone 28-8 (Bristol-Myers Squibb) , clones SP263 (Roche) , SP142 (Spring Biosciences) , and clone E1L3N (Cell Signaling Technology) .
  • a preferred anti-PD-L1 antibody is clone SP263 (Roche)
  • another preferred anti-PD-L1 antibody is clone E1L3N (Cell Signaling Technology) .
  • Clone 22C3 is a well-known, commercially available anti-PD-L1 antibody described e.g., in US 9,709,568 B2, which disclosure is incorporated by reference in its entirety.
  • Clone 22C3 comprises a heavy and light chain variable region, wherein the heavy chain variable region comprises: (i) a complementarity-determining region 1 (HCDR1) whose amino acid sequence is shown in SEQ ID NO: 23, (ii) a complementarity-determining region 2 (HCDR2) whose amino acid sequence is shown in SEQ ID NO: 24, and (iii) a complementarity-determining region 3 (HCDR3) whose amino acid sequence is shown in SEQ ID NO: 25; and the light chain variable region comprises: (i) a complementarity-determining region 1 (LCDR1) whose amino acid sequence is shown in SEQ ID NO: 20, (ii) a complementarity-determining region 2 (LCDR2) whose amino acid sequence is shown in SEQ ID NO: 21, and (iii) a complementarity-determining region 3 (LCDR3) whose amino acid sequence is shown in SEQ ID NO: 22.
  • the heavy and light chain variable regions are set forth in SEQ ID NO: 27 and 26.
  • Clone 28-8 is a well-known commercially available anti-PD-L1 antibody described e.g., in US 9,212,224 B2, which disclosure is incorporated by reference in its entirety.
  • Clone 28-8 comprises a heavy and light chain variable region (i.e., VH and VL) set forth in SEQ ID NO: 28 and 29.
  • SP263 is a well-known commercially available anti-PD-L1 antibody described e.g., in US 2010/0343556 A1
  • Clone SP263 comprises a heavy and light chain variable region, wherein the heavy chain variable region comprises: (i) a complementarity-determining region 1 (HCDR1) whose amino acid sequence is shown in SEQ ID NO: 33, (ii) a complementarity-determining region 2 (HCDR2) whose amino acid sequence is shown in SEQ ID NO: 34, and (iii) a complementarity-determining region 3 (HCDR3) whose amino acid sequence is shown in SEQ ID NO: 35; and the light chain variable region comprises: (i) a complementarity-determining region 1 (LCDR1) whose amino acid sequence is shown in SEQ ID NO: 30, (ii) a complementarity-determining region 2 (LCDR2) whose amino acid sequence is shown in SEQ ID NO: 31, and (iii) a complementarity-determining region 3 (LCDR3) whose amino acid sequence is shown in SEQ ID NO: 32.
  • the heavy and light chain variable region are set forth in SEQ ID NO: 36 and 37.
  • a target specific binding agent is a nucleic acid or nucleic acid binding agent, e.g., as employed in in situ hybridization (ISH) reactions.
  • the target binding reagent can be a DNA, RNA, DNA/RNA hybrid molecule, peptide nucleic acid (PNA) , and the like. No limitation in the metes and bounds of a target-specific binding agent that finds use in the subject disclosure is intended.
  • the target-specific binding agent (or any secondary reagent used to detect the target-specific binding agent) may be attached to any suitable detectable label (or chromogen) or enzyme capable of producing a detectable label.
  • the first or second label is produced by an enzymatic reaction, e.g., by the activity of horseradish peroxidase, alkaline phosphatase, and the like. Any convenient enzymatic label/chromogen deposition system can be employed (e.g., as used in standard IHC methods) , and as such, no limitation in this regard is intended.
  • the detectable label is a fluorescent tag.
  • the staining reagents used may include a target-specific antibody (e.g., a PD-L1 specific antibody) .
  • the staining reagents used may include one or more additional antibodies that each bind to a different antigen.
  • a set of antibodies may include a first antibody that binds to a first antigen (e.g., PD-L1) , a second antibody that binds to a second antigen, optionally a third antibody that binds to a third antigen and, optionally a fourth antibody that binds to a fourth antigen and/or further antibodies that bind to further antigens.
  • the antibody/antibodies used are primary antibodies that are detected by use of a secondary antibody (or other reagent) .
  • the staining steps thus may be done by incubating the cells of the tissue sample, e.g., a tissue section or cell suspension, with the primary antibody/antibodies and then, after the primary antibody has bound to the desired target in/on the cells, incubating the cells with the labeled secondary antibody/antibodies (e.g., as is done in standard IHC protocols) .
  • each of the primary antibodies for each different target is from a different species (e.g., goat, rabbit, mouse, camel, chicken, donkey, etc. ) and the corresponding secondary antibodies specific for each different primary antibody are distinguishably labeled from each other.
  • the viable tumour cells and the number of lymphocytes and macrophages are counted in the tumour nests and the adjacent supporting stroma of the tumour tissue sample.
  • the maximum score is preferably defined as 100 and a minimum of 100 viable tumour cells are preferably required to calculate the score. See Park et al. Cancer Res. Treat., 2020; 52 (3) : 661-670 and Yamashita et al., Gastric Cancer, 2020, 23: 95-104.
  • an in vitro diagnostic device (IVD) bridging study can be performed to determine whether that scoring algorithm defines a similar PD-L1 expression score as the established CPS.
  • IVD in vitro diagnostic device
  • a test for determining PD-L1 expression score other than the CPS companion diagnostic can be used, if it can be demonstrated that the other IVD companion diagnostic has performance characteristics that are very similar to those of the CPS companion diagnostic. This is generally demonstrated through a bridging study between the two tests, using the original clinical trial samples and a pre-specified statistical analysis plan, to show that results with the candidate IVD companion diagnostic are very similar to those of the CPS companion diagnostic.
  • a bridging study can evaluate efficacy of the therapeutic product in subjects whose marker status is determined by the candidate IVD companion diagnostic by assessing both concordance and discordance between the two tests using the same specimens from subjects who were tested for trial eligibility. The analysis needs to consider any potential impact of missing samples not available for the concordance study.
  • the ability of the candidate IVD companion diagnostic to predict the efficacy of the therapeutic product can be supported indirectly by high analytical concordance with the CPS companion diagnostic on a large number of representative samples, including samples from subjects excluded from the trial because they were marker-negative by the CPS companion diagnostic.
  • the assessment of the clinical validity of the candidate IVD companion diagnostic can rely on extrapolating the clinical performance characteristics of the CPS companion diagnostic to the clinical performance characteristics of the candidate IVD companion diagnostic.
  • the ideal bridging study is one in which all samples tested with the trial test are retested with the candidate IVD companion diagnostic and valid test results are obtained and used to assess comparative performance.
  • a bridging study with specimens from an all-comers trial also allows an analysis of efficacy using the results of the candidate IVD companion diagnostic. Note, however, that care should preferably be taken in understanding the analytical performance of the IVD prior to the bridging study because adjustments to the IVD should not be made from results obtained with the clinical trial samples. Whether a clinical trial enrolls subjects irrespective of the test result or enrolls only the subset of subjects identified by the test result, both the test-negative and test-positive clinical trial samples should preferably be included in bridging studies to avoid bias due to prescreening.
  • the characteristics of the subset adequately reflect the characteristics that affect test performance (e.g., tumour size, histology, melanin content, necrotic tissue, resected tissue versus core needle biopsy) and that the characteristics of the subjects that may affect therapeutic product efficacy (e.g., patient demographics, stage of disease, stratification factors) are proportionally preserved in the retest sample set when compared to the samples in the original set.
  • test performance e.g., tumour size, histology, melanin content, necrotic tissue, resected tissue versus core needle biopsy
  • therapeutic product efficacy e.g., patient demographics, stage of disease, stratification factors
  • a re-analysis of the primary outcome data should preferably be made according to the final test results with the retest sample set in order to assure that any reclassification that occurs does not alter conclusions about the safety and efficacy of the therapeutic product in the selected population.
  • a second re-analysis can be conducted in which missing data for the final test are imputed.
  • the nature of the re-analysis will be product-specific and may be discussed with the appropriate IVD review center.
  • additional analytical validation can potentially be requested to support satisfactory concordance across methods where discordance may arise, e.g., precision, limit of detection, and accuracy. In the event there is discordance in a marker-positive-only trial, it is possible that the candidate IVD companion diagnostic will more accurately predict responders, a difference that would represent an advantage for optimal use of the therapeutic product.
  • the TAP has performance characteristics that are very similar to those of the CPS companion diagnostic using the described bridging study.
  • a PD-L1 expression score determined using different anti-PD L1 antibodies such as SP263 or 22C3 or E1L3N.
  • a PD-L1 expression score obtained from using 22C3 and the CPS scoring algorithm has characteristics that are very similar to those of a PD-L1 expression score obtain from using 28-8 and the CPS scoring algorithm using the described bridging study.
  • the bispecific antibody and the chemotherapy are separately administered. In some embodiments, a dosage of the bispecific antibody and a dosage of the chemotherapy are separately administered. In some embodiments, a dosage of the bispecific antibody and a dosage of the chemotherapy are administered using a single composition.
  • a dosage of the bispecific antibody and a dosage of the chemotherapy are administered concurrently or consecutively.
  • enteral route refers to the administration via any part of the gastrointestinal tract.
  • enteral routes include oral, mucosal, buccal, and rectal route, or intragastric route.
  • Parenteral route refers to a route of administration other than enteral route.
  • parenteral routes of administration examples include intravenous, intramuscular, intradermal, intraperitoneal, intratumour, intravesical, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, transtracheal, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrastemal, subcutaneous, or topical administration.
  • the bispecific antibody and the chemotherapy of the disclosure can be administered using any suitable method, such as by oral ingestion, nasogastric tube, gastrostomy tube, injection, infusion, implantable infusion pump, and osmotic pump.
  • treatment regimen “dosing protocol, ” and “dosing regimen” are used interchangeably to refer to the dosage and timing of administration of each dosage bispecific antibody and the chemotherapy in a combination therapy of the disclosure.
  • the bispecific antibody and/or the chemotherapy is administered intravenously, preferably wherein the bispecific antibody and the chemotherapy are administered intravenously.
  • the bispecific antibody and/or the chemotherapy is administered via an IV injection or IV infusion.
  • the bispecific antibody and the chemotherapy are administered via an IV injection or IV infusion.
  • the bispecific antibody and the chemotherapy can be administered concurrently or consecutively via an IV infusion.
  • the bispecific antibody is administered in a step-up dosing regimen to a subject or patient, e.g., with a first and one or more subsequent dose regimens.
  • the dosage of the bispecific antibody is lower than the dosage of the bispecific antibody in a second dose regimen.
  • the dosage of the bispecific antibody in each subsequent dosage regimen is higher compared to the dosage of the bispecific antibody in the dose regimen that precedes each subsequent dose regimen.
  • the dosage of the chemotherapeutic agent may be the same in the first and one or more subsequent dose regimens.
  • the dosage of the chemotherapeutic agent in the first dose regimen may be lower than the dosage of the chemotherapeutic agent in a second dose regimen. If the chemotherapeutic agent is administered in more than two dose regimens in some embodiment of the afore mentioned examples, the dosage of the chemotherapeutic agent in each subsequent dosage regimen may be higher compared to the dosage of the chemotherapeutic agent in the dose regimen that precedes each subsequent dose regimen.
  • the subject has been determined to have a PD-L1 expression score before the treatment as determined by the combined positive score (CPS) of ⁇ 30, preferably ⁇ 20, more preferably ⁇ 10, and most preferably ⁇ 10 or even ⁇ 1 or other integrating scoring algorithm defining a similar PD-L1 expression score such as TPS or TAP, preferably TAP.
  • CPS combined positive score
  • the subject has been preferably determined to have a PD-L1 expression score before the treatment as determined by a CPS of up to 20, preferably from 1 to 20 or > 0 to 20, more preferably from 1 to ⁇ 10, such as 1 to 9, or other integrating scoring algorithm defining a similar PD-L1 expression score.
  • the subject has been determined to have a PD-L1 expression score as determined by a CPS from 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, or 1 to 3 or other integrating scoring algorithm defining a similar PD-L1 expression score.
  • the subject has a PD-L1 expression score as determined by a CPS of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, preferably a CPS of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, more preferably a CPS of 1, 2, 3, 4, 5, 6, 7, 8, or 9 or other integrating scoring algorithm defining a similar PD-L1 expression score such as TPS or TAP.
  • the subject has been determined to have a PD-L1 expression score as determined by CPS of ⁇ 10, ⁇ 9, ⁇ 8, ⁇ 7, ⁇ 6, ⁇ 5, ⁇ 4, or ⁇ 3 before the treatment or other integrating scoring algorithm defining a similar PD-L1 expression score such as TPS or TAP.
  • the subject has been determined to have a PD-L1 expression score as determined by CPS of > 0 before the treatment or other integrating scoring algorithm defining a similar PD-L1 expression score such as TPS or TAP.
  • the subject is part of a patient group to be treated with the combination therapy disclosed herein.
  • this patient group comprises one or more subjects having a PD-L1 expression score as determined by a CPS of ⁇ 30, preferably ⁇ 20, more preferably ⁇ 10, and most preferably ⁇ 10 or even ⁇ 1, before the treatment or other integrating scoring algorithm defining a similar PD-L1 expression score such as TPS or TAP.
  • This patient group may further comprise one or more subjects having a PD-L1 expression score as determined by a CPS of > 30, preferably >20, more preferably > 10, and most preferably ⁇ 10 or other integrating scoring algorithm defining a similar PD-L1 expression score such as TPS or TAP.
  • the bispecific antibody is administered in a dosage ranging from 0.1 mg/kg to 45 mg/kg body weight, preferably 1 mg/kg to 30 mg/kg body weight per treatment.
  • the treatment comprises repeated treatments, wherein the treatment cycle is repeated at least 1, 2, 3, 4, 5, 6, 7, or 8 times, wherein each cycle preferably has up to 30, preferably 28 days or 21 days. However, the treatment can be continued until disease progression or the initiation of a new anti-tumour treatment.
  • the subject has not been previously treated for cancer, i.e., is treatment naive. In some embodiments, the subject has been previously treated for cancer, in particular the subject has had at least one previous chemotherapy treatment.
  • the subject has not been previously treated with a PD-1/PD-L1 inhibitor, such as pembrolizumab or atezolizumab.
  • a PD-1/PD-L1 inhibitor such as pembrolizumab or atezolizumab.
  • the subject had one or more been previous treatments with a PD-1/PD-L1 inhibitor, such as pembrolizumab or atezolizumab.
  • a PD-1/PD-L1 inhibitor such as pembrolizumab or atezolizumab.
  • the bispecific antibody is administered every 6 weeks, preferably every 4 weeks, more preferably every 3 weeks, and most preferably every 2 weeks.
  • the bispecific antibody is administered every 2 weeks at a dosage ranging from 10 mg/kg to 30 mg/kg, preferably ranging from 15 mg/kg to 25 mg/kg, more preferably being 20 mg/kg.
  • the bispecific antibody is administered every 3 weeks at a dosage ranging from 20 mg/kg to 40 mg/kg, preferably ranging from 25 mg/kg to 35 mg/kg, more preferably being 30 mg/kg.
  • the chemotherapy is administered once or more within the first 20 days or the first 21 days of each cycle, wherein the chemotherapy is administered twice or more within the first 20 days or the first 21 days of each cycle, more preferably wherein the chemotherapy is administered at least thrice within the first 20 days or the first 21 days of each cycle.
  • the chemotherapy is administered once or more within the first 14 days or the first 15 days of each cycle, wherein the chemotherapy is administered twice or more within the first 14 days or the first 15 days of each cycle, more preferably wherein the chemotherapy is administered at least thrice within the first 14 days or the first 15 days of each cycle.
  • the chemotherapy can be administered on the 1 st , 8 th , and 15 th day of each cycle, wherein each cycle has 21 days.
  • the treatment method disclosed herein results in increased overall survival in said subject compared to the chemotherapy or the bispecific antibody or an anti-PD-L1 antibody or an anti-PD-1 antibody treatment alone or compared to a standard treatment comprising the chemotherapy and an anti-PD-L1 antibody or chemotherapy and an anti-PD-1 antibody, wherein the anti-PD-L1 antibody is preferably atezolizumab and the anti-PD-1 antibody is preferably pembrolizumab.
  • the treatment method disclosed herein results in increased median progression-free survival said subject compared to the chemotherapy or the bispecific antibody or anti-PD-L1 antibody or anti-PD-1 antibody treatment alone or compared to a standard treatment comprising the chemotherapy and the anti-PD-L1 antibody or the chemotherapy and the anti-PD-1 antibody, wherein the anti-PD-L1 antibody is preferably atezolizumab and the anti-PD-1 antibody is preferably pembrolizumab.
  • the cancer is a solid tumour.
  • the cancer is selected from the group consisting of melanoma, lung, liver, stomach, renal cell, urothelial, cervical, colorectal, ovarian, colon, breast, esophagus, mesothelioma, and head and neck cancers, preferably the cancer is selected from urothelial, breast and esophagus cancer.
  • the cancer can be selected from non-small cell lung cancer (NSCLC) , small cell lung cancer (SCLC) including extensive stage small cell lung cancer and limited stage small cell lung cancer, urothelial carcinoma, esophageal cancer, head and neck squamous cell carcinoma (HNSCC) , triple-negative breast cancer (TNBC) , or cervical cancer.
  • NSCLC non-small cell lung cancer
  • SCLC small cell lung cancer
  • HNSCC head and neck squamous cell carcinoma
  • TNBC triple-negative breast cancer
  • the cancer can preferably be TBNC, gastric adenocarcinoma, gastroesophageal junction (GEJ) adenocarcinoma, esophageal squamous-cell carcinoma, cervical cancer, urothelial carcinoma, or HNSCC. Most preferably, the cancer is TBNC.
  • the TNBC may be a TNBC of the subtype (1) luminal androgen receptor (LAR) , (2) immunomodulatory (IM) , (3) basal-like immune-suppressed (BLIS) , or (4) mesenchymal-like (MES) according to the Fudan University Shanghai Cancer Center (FUSCC) classification (see Jiang YZ, Ma D, Suo C, et al. Genomic and transcriptomic landscape of triple-negative breast cancers: subtypes and treatment strategies. Cancer Cell. 2019; 35 (3) : 428-440. e5) , preferably TNBC of the subtype IM or MES.
  • the cancer is small cell lung cancer (SCLC) , non-small cell lung cancer (NSCLC) or triple-negative breast cancer (TNBC) , preferably the cancer is triple-negative breast cancer, for example advanced or metastatic triple-negative breast cancer.
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • TNBC triple-negative breast cancer
  • the cancer is triple-negative breast cancer, for example advanced or metastatic triple-negative breast cancer.
  • the NSCLC has a squamous histology. In some embodiments, the NSCLC has a non-squamous histology. In some embodiments, the NCLC is an EGFR mutation-positive NSCLC.
  • the bispecific antibody comprises an anti-PD-L1 antibody or fragment thereof. In some preferred embodiments, the bispecific antibody comprises an anti-VEGF antibody or fragment thereof, preferably an anti-VEGF-A antibody or fragment thereof.
  • the bispecific antibody comprises a Fab, F’ b', F (ab') 2, Fd, Fv, sdAb, complementarity determining region fragment, single chain antibody, humanized antibody, chimeric antibody or diabody antibody, preferably a single domain antibody, more preferably a VHH.
  • the bispecific antibody comprises two anti-PD-L1 single domain antibodies, preferably two VHHs, preferably fused to the N-or C-terminus of the anti-VEGF antibody heavy or light chain. In some embodiments, the bispecific antibody comprises two anti-PD-L1 single domain antibodies, preferably two VHHs, preferably fused to the C-terminus of the anti-VEGF antibody heavy chain.
  • the anti-PD-L1 antibody or fragment thereof is a monovalent or bivalent antibody or fragment thereof. In some embodiments, the anti-VEGF antibody or fragment thereof is a monovalent or bivalent antibody or fragment thereof,
  • the bispecific antibody comprises an anti-PD-L1 single domain antibody comprising a heavy chain variable region
  • the heavy chain variable region comprises: (i) a complementarity-determining region 1 (HCDR1) whose amino acid sequence is shown in SEQ ID NO: 1, (ii) a complementarity-determining region 2 (HCDR2) whose amino acid sequence is shown in SEQ ID NO: 2, and (iii) a complementarity-determining region 3 (HCDR3) whose amino acid sequence is shown in SEQ ID NO: 3, or a variant thereof having up to three, e.g.
  • IMGT numbering system see Ehrenmann F, Kaas Q, Lefranc M P. IMGT/3Dstructure-DB and IMGT/DomainGapAlign: a database and a tool for immunoglobulins or antibodies, T cell receptors, MHC, IgSF and MhcSF [J] . Nucleic acids research, 2009; 38 (suppl_1) : D301-D307) .
  • the bispecific antibody comprises an anti-PD-L1 single domain antibody comprising a heavy chain variable region
  • the heavy chain variable region comprises: (i) a complementarity-determining region 1 (HCDR1) whose amino acid sequence is shown in SEQ ID NO: 18, (ii) a complementarity-determining region 2 (HCDR2) whose amino acid sequence is shown in SEQ ID NO: 19, and (iii) a complementarity-determining region 3 (HCDR3) whose amino acid sequence is shown in SEQ ID NO: 38, or a variant thereof having up to three, e.g. one or two, amino acid substitutions, additions or deletions, wherein the CDRs are defined according to the Kabat numbering system.
  • HCDR1 complementarity-determining region 1
  • HCDR2 complementarity-determining region 2
  • HCDR3 complementarity-determining region 3
  • the CDR variant has up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR variant has up to one amino acid substitution, addition or deletion. In some embodiments, the CDR variant has up to three amino acid substitutions. In some embodiments, the CDR variant has up to two amino acid substitutions. In some embodiments, the CDR variant has up to one amino acid substitution.
  • the amino acid sequence of the anti-PD-L1 single domain antibody is shown in SEQ ID NO: 9.
  • the amino acid sequence of the anti-PD-L1 single domain antibody has at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%identity to SEQ ID NO: 9 and/or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and/or substitutions in a framework region thereof.
  • the bispecific antibody can comprise one anti-VEGF antibody and two anti-PD-L1 single domain antibodies, preferably fused to the C-terminus of the anti-VEGF antibody, wherein each of these anti-PD-L1 single domain antibodies comprises or consists of the amino acid sequence shown in SEQ ID NO: 9 or wherein the amino acid sequence of the anti-PD-L1 single domain antibody has at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%identity to SEQ ID NO: 9
  • the amino acid sequence of the anti-PD-L1 single domain antibody has at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%identity to SEQ ID NO: 9 and/or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and/or substitutions in a framework region thereof.
  • the anti-PD-L1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 9, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%identity thereto and/or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and/or substitutions in a framework region thereof, and comprises a heavy chain variable region comprising: a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 1; a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 2; and a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 3.
  • a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 1
  • a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 2
  • a HCDR3 comprising or consisting of the amino
  • the anti-PD-L1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 9, or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%identity thereto and/or one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) amino acid additions, deletions and/or substitutions in a framework region thereof, and comprises a heavy chain variable region comprising: a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 18; a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 19; and a HCDR3 comprising or consisting of the amino acid sequence of SEQ ID NO: 38.
  • a HCDR1 comprising or consisting of the amino acid sequence of SEQ ID NO: 18
  • a HCDR2 comprising or consisting of the amino acid sequence of SEQ ID NO: 19
  • a HCDR3 comprising or consisting of the
  • the anti-PD-L1 antibody or fragment thereof comprises or consists of the amino acid sequence of SEQ ID NO: 9. In some embodiments, the anti-PD-L1 antibody or fragment thereof consists of the amino acid sequence of SEQ ID NO: 9.
  • the bispecific antibody specifically binds to VEGF-A.
  • the anti-VEGF antibody or fragment thereof comprises a constant region preferably derived from a human antibody, preferably, the constant region is selected from the constant region of human IgG1, IgG2, IgG3 or IgG4.
  • the anti-VEGF-A antibody or fragment thereof comprises a constant region preferably derived from a human antibody, preferably, the constant region is selected from the constant region of human IgG1, IgG2, IgG3 or IgG4.
  • the anti-VEGF antibody or fragment thereof comprises an Fc region comprising one or more mutations which reduce or abolish immune effect functions.
  • Suitable mutations are known in the art and may include one or more amino acid substitutions (see e.g. Wilkinson, I., et al., 2021. FcPLoS One, 16 (12) , p. e0260954; and Liu, R., et al., 2020. Antibodies, 9 (4) , p. 64) .
  • the anti-VEGF antibody or fragment thereof comprises an IgG1 Fc region comprising a L234A (with the numbering according to the EU-index) and/or a L235A mutation (with the numbering according to the EU-index) .
  • the anti-VEGF antibody or fragment thereof comprises an IgG1 Fc region comprising L234A and L235A mutations (with the numbering according to the EU-index) .
  • amino acids are numbered according to the Eu numbering (Eu-index) as set forth in Kabat (Kabat, E. A. ; National Institutes of Health (U. S. ) Office of the Director. Sequences of Proteins of Immunological Interest, 5th ed.; DIANE Publishing: Collingdale, PA, USA, 1991) .
  • the anti-VEGF antibody or fragment thereof comprises a IgG1 Fc region, preferably having the amino acid sequence shown in SEQ ID NO: 13.
  • the anti-VEGF-A antibody or fragment thereof comprises a IgG1 Fc region, preferably having the amino acid sequence shown in SEQ ID NO: 13 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%identity to the amino acid sequence shown in SEQ ID NO: 13.
  • each anti-PD-L1 single domain antibody may be fused to the anti-VEGF antibody by any suitable method.
  • each anti-PD-L1 single domain antibody is terminally-fused to the anti-VEGF antibody.
  • each anti-PD-L1 single domain antibody is fused to: (i) the C-terminus of a heavy chain; (ii) the N-terminus of a heavy chain; (iii) the C-terminus of a light chain; or (iv) the N-terminus of a light chain.
  • each anti-PD-L1 single domain antibodies is fused to the C-terminus of an anti-VEGF antibody, preferably the C-terminus of a heavy chain.
  • the bispecific antibody preferably comprises an anti-VEGF antibody and two anti-PD-L1 VHHs, wherein each heavy chain of the anti-VEGF antibody is fused to an anti-PD-L1 VHH.
  • the VHH can be fused to the anti-VEGF antibody by a linker, for example a glycine and serine-rich linker (GS-linker) or any suitable linker known in the art.
  • a linker for example a glycine and serine-rich linker (GS-linker) or any suitable linker known in the art.
  • An example linker is provided by SEQ ID NO: 14 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%identity to the amino acid sequence shown in SEQ ID NO: 14.
  • the anti-VEGF antibody or fragment thereof comprises a CL, preferably having the amino acid sequence shown in SEQ ID NO: 15 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%identity to the amino acid sequence shown in SEQ ID NO: 15.
  • the anti-VEGF antibody or fragment thereof comprises a CH1, preferably having the amino acid sequence shown in SEQ ID NO: 12 or an amino acid sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%identity to the amino acid sequence shown in SEQ ID NO: 12.
  • the anti-VEGF antibody comprises a heavy and light chain variable region, wherein the heavy chain variable region comprises: (i) a complementarity-determining region 1 (HCDR1) whose amino acid sequence is shown in SEQ ID NO: 4, (ii) a complementarity-determining region 2 (HCDR2) whose amino acid sequence is shown in SEQ ID NO: 5, and (iii) a complementarity-determining region 3 (HCDR3) whose amino acid sequence is shown in SEQ ID NO: 6, or a variant thereof having up to three e.g. one or two, amino acid substitutions, additions or deletions; and
  • the light chain variable region comprises: (i) a complementarity-determining region 1 (LCDR1) whose amino acid sequence is shown in SEQ ID NO: 7, (ii) a complementarity-determining region 2 (LCDR2) whose amino acid sequence is shown in SEQ ID NO: 44, and (iii) a complementarity-determining region 3 (LCDR3) whose amino acid sequence is shown in SEQ ID NO: 8, or a variant thereof having up to three, e.g. one or two, amino acid substitutions, additions or deletions.
  • LCDR1 complementarity-determining region 1
  • LCDR2 complementarity-determining region 2
  • LCDR3 complementarity-determining region 3
  • IMGT/3Dstructure-DB and IMGT/DomainGapAlign a database and a tool for immunoglobulins or antibodies, T cell receptors, MHC, IgSF and MhcSF [J] . Nucleic acids research, 2009; 38 (suppl_1) : D301-D307) .
  • the anti-VEGF antibody comprises a heavy and light chain variable region, wherein the heavy chain variable region comprises: (i) a complementarity-determining region 1 (HCDR1) whose amino acid sequence is shown in SEQ ID NO: 39, (ii) a complementarity-determining region 2 (HCDR2) whose amino acid sequence is shown in SEQ ID NO: 40, and (iii) a complementarity-determining region 3 (HCDR3) whose amino acid sequence is shown in SEQ ID NO: 41, or a variant thereof having up to three e.g.
  • HCDR1 complementarity-determining region 1
  • HCDR2 complementarity-determining region 2
  • HCDR3 complementarity-determining region 3
  • the light chain variable region comprises: (i) a complementarity-determining region 1 (LCDR1) whose amino acid sequence is shown in SEQ ID NO: 42, (ii) a complementarity-determining region 2 (LCDR2) whose amino acid sequence is shown in SEQ ID NO: 43, and (iii) a complementarity-determining region 3 (LCDR3) whose amino acid sequence is shown in SEQ ID NO: 8, or a variant thereof having up to three, e.g. one or two, amino acid substitutions, additions or deletions.
  • LCDR1 complementarity-determining region 1
  • LCDR2 complementarity-determining region 2
  • LCDR3 complementarity-determining region 3
  • the CDR variant has up to two amino acid substitutions, additions or deletions. In some embodiments, the CDR variant has up to one amino acid substitution, addition or deletion. In some embodiments, the CDR variant has up to three amino acid substitutions. In some embodiments, the CDR variant has up to two amino acid substitutions. In some embodiments, the CDR variant has up to one amino acid substitution.
  • the amino acid sequence of the heavy chain variable region of the anti-VEGF antibody (or anti-VEGF-A antibody) is shown in SEQ ID NO: 10, and the amino acid sequence of the light chain variable region of the anti-VEGF antibody is shown in SEQ ID NO: 11; or wherein the amino acid sequence of the heavy chain variable region of the anti-VEGF antibody has at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%identity to SEQ ID NO: 10, and the amino acid sequence of the light chain variable region of the anti-VEGF antibody has at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%identity to SEQ ID NO: 11.
  • the amino acid sequence of the heavy chain of the bispecific antibody is shown in SEQ ID NO: 16, and the amino acid sequence of the light chain variable region of the bispecific antibody is shown in SEQ ID NO: 17; or wherein the amino acid sequence of the heavy chain of the bispecific antibody has at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%identity to SEQ ID NO: 16, and the amino acid sequence of the light chain variable region of the bispecific antibody has at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%identity to SEQ ID NO: 17.
  • the anti-VEGF-A antibody is bevacizumab.
  • the bispecific antibody is encoded by one or more nucleic acid molecules.
  • the bispecific antibody can preferably comprise:
  • two anti-PD-L1 single domain antibodies each comprising a heavy chain variable region, and the heavy chain variable region comprises: (i) a complementarity-determining region 1 (HCDR1) whose amino acid sequence is shown in SEQ ID NO: 1, (ii) a complementarity-determining region 2 (HCDR2) whose amino acid sequence is shown in SEQ ID NO: 2, and (iii) a complementarity-determining region 3 (HCDR3) whose amino acid sequence is shown in SEQ ID NO: 3; and
  • an anti-VEGF-A antibody comprising a heavy chain variable region comprising:
  • HCDR1 complementarity-determining region 1
  • HCDR2 complementarity-determining region 2
  • HCDR3 complementarity-determining region 3
  • a light chain variable region comprising: (i) a complementarity-determining region 1 (LCDR1) whose amino acid sequence is shown in SEQ ID NO: 7, (ii) a complementarity-determining region 2 (LCDR2) whose amino acid sequence is shown in SEQ ID NO: 44, and (iii) a complementarity-determining region 3 (LCDR3) whose amino acid sequence is shown in SEQ ID NO: 8.
  • LCDR1 complementarity-determining region 1
  • LCDR2 complementarity-determining region 2
  • LCDR3 complementarity-determining region 3
  • bispecific antibody or bispecific antibody variants are described in WO 2022/042719, which disclosure is hereby incorporated in its entirety.
  • the bispecific antibody can be linked or produced by various methods, see, for example, the method of Songsivilai et al. (Clin. Exp. Immunol., 79: 315-321 (1990) ) , and the method of Kostelny et al. (J. Immunol., 148: 1547-1553 (1992) which disclosures are also hereby incorporated in their entirety.
  • the bispecific antibody is conjugated with a chemotherapeutical agent to obtain an immunoconjugate.
  • the immunoconjugate contains:
  • conjugation moiety selected from the group consisting of detectable labels, drugs, toxins, cytokines, radionuclides, or enzymes, gold nanoparticles/nanorods, nanomagnetic particles, viral coat proteins or VLPs, or their combination.
  • the radionuclide includes:
  • a diagnostic isotope selected from the group consisting of Tc-99m, Ga-68, F-18, I-123, I-125, I-131, In-111, Ga-67, Cu-64, Zr-89, C-11, Lu-177, Re-188, or a combination thereof; and/or
  • a therapeutic isotope selected from the group consisting of Lu-177, Y-90, Ac-225, As-211, Bi-212, Bi-213, Cs-137, Cr-51, Co-60, Dy-165, Er-169, Fm-255, Au-198, Ho-166, I-125, I-131, Ir-192, Fe-59, Pb-212, Mo-99, Pd-103, P-32, K-42, Re-186, Re-188, Sm-153, Ra223, Ru-106, Na24, Sr89, Tb-149, Th-227, Xe-133Yb-169, Yb-177, or a combination thereof.
  • Typical cytotoxic drugs include, for example, auristatins, camptothecins, duocarmycins, etoposides, maytansines and maytansinoids (eg DM1 and DM4) , taxanes (taxanes) , benzodiazepines, or benzodiazepine containing drugs (eg, pyrrolo [1, 4] benzodiazepines (PBDs) , indoline benzodiazepines indolinobenzodiazepines and oxazolidinobenzodiazepines) , vinca alkaloids, or combinations thereof.
  • auristatins camptothecins, duocarmycins, etoposides
  • maytansines and maytansinoids eg DM1 and DM4
  • taxanes taxanes
  • benzodiazepines or benzodiazepine containing drugs (eg, pyrrolo [1, 4] benzodiazepines (PBDs)
  • the toxin is selected from the following group: Auristatins (e.g., auristatin E, auristatin F, MMAE, and MMAF) , chlortetracycline, maytansoid, gamatoxin, gamatoxin A-chain, combretastatin, docarmicin, Lastatin, doxorubicin, daunorubicin, paclitaxel, cisplatin, cc1065, ethidium bromide, mitomycin, etoposide, tenoposide, vincristine, vinblastine, autumn Narcissin, Dihydroxyanthraxdione, Actinomycin, Diphtheria Toxin, Pseudomonas Exotoxin (PE) A, PE40, Acacia toxin, Acacia A chain, Capsule root toxin A chain, ⁇ -Sarcinus, gelonin, mitogellin, ret
  • the methods of treating disclosed herein comprise a chemotherapy.
  • the chemotherapy comprises one or more platinum-based chemotherapeutic agents.
  • the one or more platinum-based chemotherapeutic agents is carboplatin, cisplatin, oxaliplatin, or combinations thereof.
  • the chemotherapy comprises one or more antimetabolite-based chemotherapy agents.
  • the one or more antimetabolite-based chemotherapeutic agent is gemcitabine.
  • chemotherapy comprises one or more platinum-based chemotherapeutic agents in combination with one or more antimetabolite-based chemotherapy agents.
  • the chemotherapy comprises cisplatin and gemcitabine.
  • the bispecific antibody is administered concurrently with chemotherapy.
  • the bispecific antibody and chemotherapy are administered within up to 15 days of each other. In some embodiments, the bispecific antibody and chemotherapy are administered within about two days of each other. In some embodiments, the bispecific antibody and chemotherapy are administered within about one day of each other. In some embodiments, the bispecific antibody and chemotherapy are administered concurrently (for example by simultaneous (same day) administration) . In some embodiments, the bispecific antibody is administered on day 1 of the chemotherapy treatment cycle.
  • the observed toxicities of the treatment with the bispecific antibody and chemotherapy combination are similar to those commonly seen with either chemotherapy or immunotherapy alone.
  • the chemotherapy comprises a chemotherapy agent selected from lurbinectedin, topotecan, taxane, such as paclitaxel, nanoparticle albumin-bound paclitaxel (nab-paclitaxel) or docetaxel, pemetrexed, 5-fluoruracil, irinotecan, etoposide, gemcitabine, anthracyclines, capecitabine, vinorelbine, eribulin, ixabepilone or combinations thereof.
  • a chemotherapy agent selected from lurbinectedin, topotecan, taxane, such as paclitaxel, nanoparticle albumin-bound paclitaxel (nab-paclitaxel) or docetaxel, pemetrexed, 5-fluoruracil, irinotecan, etoposide, gemcitabine, anthracyclines, capecitabine, vinorelbine, eribulin, ixabepilone or combinations thereof.
  • the chemotherapy comprises a chemotherapy agent selected from topotecan, taxane, such as paclitaxel, nanoparticle albumin-bound paclitaxel (nab-paclitaxel) or docetaxel, pemetrexed, 5-fluoruracil, irinotecan, etoposide, gemcitabine, anthracyclines, capecitabine, vinorelbine, eribulin, ixabepilone or combinations thereof.
  • a chemotherapy agent selected from topotecan, taxane, such as paclitaxel, nanoparticle albumin-bound paclitaxel (nab-paclitaxel) or docetaxel, pemetrexed, 5-fluoruracil, irinotecan, etoposide, gemcitabine, anthracyclines, capecitabine, vinorelbine, eribulin, ixabepilone or combinations thereof.
  • the platinum-based chemotherapy comprises cisplatin, oxaliplatin or carboplatin.
  • the method of treatment comprises administering the bispecific antibody in combination with paclitaxel, lurbinectedin, or topotecan. In some preferred embodiments, the method of treatment comprises administering the bispecific antibody in combination with paclitaxel or topotecan.
  • the cancer is small cell lung cancer and, preferably, the method of treatment can be a second line cancer treatment. In a particularly preferred embodiment, the method of treatment comprising administering to a patient suffering from advanced small cell lung cancer as second line treatment the bispecific antibody every 3 weeks at a dosage of 20 mg/kg or 30 mg/kg in combination with paclitaxel every 3 weeks at a dosage of 175 mg/m 2 .
  • the combination may be administered for five cycles followed by the administration of the bispecific antibody only as maintenance therapy.
  • the method of treatment comprising administering to a patient suffering from advanced small cell lung cancer as second line treatment the bispecific antibody every 3 weeks at a dosage of 20 mg/kg or 30 mg/kg in combination with topotecan at a dosage of 1.5 mg/m 2 administered IV or 2.3 mg/m 2 administered orally once per day on days 1 to 5 of every 3 weeks cycle.
  • the patient may have progressed during or after first-line platinum-based therapy (with or without checkpoint inhibitor therapy) .
  • the method of treatment comprises administering the bispecific antibody in combination with pemetrexed and carboplatin.
  • the cancer is a malignant mesothelioma and, preferably, the method of treatment can be a first line cancer treatment.
  • the method of treatment comprises administering the bispecific antibody in combination with pemetrexed and carboplatin. In some preferred embodiments, the method of treatment comprises administering the bispecific antibody in combination with paclitaxel and carboplatin.
  • the cancer is NSCLC, preferably the method of treatment can be a first line treatment. In one example, the cancer is non-squamous NSCLC. In another example, the cancer is squamous NSCLC. In some preferred embodiments, pemetrexed and carboplatin can be administered at a dosage of 500 mg/m 2 and AUC 5, respectively, every 3 weeks, e.g. for 4 cycles. In some such embodiments, the cancer is non-squamous NSCLC.
  • paclitaxel and carboplatin can be administered at a dosage of 200 mg/m 2 and AUC 6, respectively, every 3 weeks, e.g. for 4 cycles.
  • the cancer is squamous NSCLC.
  • the method of treatment comprises administering the bispecific antibody in combination with pemetrexed and carboplatin or in combination with a taxane, such as paclitaxel or docetaxel, preferably docetaxel.
  • the cancer is NSCLC, preferably the method of treatment can be a second line treatment.
  • the cancer is an EGFR-mutant advanced non-squamous NSCLC and, preferably, the method of treatment can be a cancer treatment following a failed EGFR-TKI treatment.
  • the method of treatment comprises administering the bispecific antibody in combination with pemetrexed and carboplatin to a patient suffering from NSCLC as second-line treatment, in particular to a patient suffering from NSCLC who progressed after EGFR-TKI treatment.
  • the bispecific antibody is administered at a dosage of 30 mg/kg plus AUC 5 mg/mL/min carboplatin and 500 mg/m 2 pemetrexed every three weeks, e.g. for 4 cycles.
  • Such a treatment may be followed by a maintenance treatment using 30 mg/kg of the bispecific antibody in combination with 500 mg/m 2 pemetrexed.
  • the method of treatment comprises administering the bispecific antibody in combination with a taxane, such as paclitaxel or docetaxel, preferably docetaxel, to a patient suffering from NSCLC, e.g. squamous NSCLC, as second-line treatment, e.g., to a patient suffering from second-line stage IV or recurrent NSLC who progressed at least one prior line of an immune-oncology (IO) comprising treatment such as an immune checkpoint inhibitor comprising treatment or chemoimmunotherapy.
  • a taxane such as paclitaxel or docetaxel, preferably docetaxel
  • the bispecific antibody is administered at a dosage range of 1400 mg to 2000 mg (1400 mg or 2000 mg preferred) plus 75 mg/m 2 docetaxel every three weeks.
  • the bispecific antibody may be administered at a dosage of 2000 mg bispecific antibody plus 75 mg/m 2 docetaxel every three weeks.
  • the bispecific antibody may be administered in a step-up dosing regimen with a first and a second dose regimen, preferably wherein the first dose regimen is 1400 mg bispecific antibody plus 60 mg/m 2 docetaxel every three weeks or 1400 mg bispecific antibody plus 75 mg/m 2 docetaxel every three weeks and the second dose regimen is 2000 mg bispecific antibody plus 75 mg/m 2 docetaxel every three weeks.
  • the method of treatment comprises administering the bispecific antibody in combination with anthracyclines, capecitabine, vinorelbine, eribulin, ixabepilone, nab-paclitaxel, paclitaxel, or gemcitabine and carboplatin, preferably nab-paclitaxel, paclitaxel, gemcitabine and carboplatin or eribulin.
  • the cancer is TNBC (e.g., advanced or metastatic TNBC) and, preferably, the method of treatment can be a first line cancer treatment or second line cancer treatment.
  • nab-paclitaxel can be administered at a dosage of 100 mg/m 2 on the 1 st , 8 th , and 15 th day of a 28-days treatment cycle (preferably in combination with the bispecific antibody at a dosage of 15 mg/kg or 20 mg/kg on the 1 st and 15 th day of a 28-days treatment cycle) .
  • paclitaxel can be administered at a dosage of 90 mg/m 2 on the 1 st , 8 th , and 15 th day of a 28-days treatment cycle (preferably in combination with the bispecific antibody at a dosage of 1400 mg on the 1 st and 15 th day of a 28-days treatment cycle) .
  • Gemcitabine and carboplatin can be administered at a dosage of 1000 mg/m 2 and AUC 2 respectively, on the 1 st and 8 th day of a 21-days treatment cycle (preferably in combination with the bispecific antibody at a dosage of 2000 mg on the 1 st day of a 21-days treatment cycle) .
  • Eribulin can be administered at a dosage of 1.4 mg/m 2 on the 1 st and 8 th day of a 21-days treatment cycle (preferably in combination with the bispecific antibody at a dosage of 2000 mg on the first day of a 21-days treatment cycle) .
  • Nab-paclitaxel can be administered at a dosage of 100 mg/m 2 on the 1 st , 8 th , and 15 th day of a 28-days treatment cycle (preferably in combination with the bispecific antibody at a dosage of 1400 mg on the 1 st and 15 th day of a 28-days treatment cycle) .
  • paclitaxel can be administered at a dosage of 90 mg/m 2 on the 1 st , 8 th , and 15 th day of a 28-days treatment cycle (preferably in combination with the bispecific antibody at a dosage of 1400 mg on the 1 st and 15 th day of a 28-days treatment cycle) .
  • gemcitabine can be administered at a dosage of 1000 mg/m 2 and carboplatin can be administered at AUC2 on the 1 st and 8 th , and 15 th day of a 21-days treatment cycle (preferably in combination with the bispecific antibody at a dosage of 2000 mg every 3 weeks) .
  • the patient may have a PD-L1 expression score before the treatment as determined by a combined positive score (CPS) of ⁇ 10 or other integrating scoring algorithm defining a similar PD-L1 expression score.
  • the treatment may be a first line cancer treatment.
  • the method of treatment comprises administering the bispecific antibody in combination with FOLFIRNOX, preferably comprising folinic acid, oxaliplatin, Irinotecan Hydrochloride, and 5-fluorouracil.
  • FOLFIRNOX preferably comprising folinic acid, oxaliplatin, Irinotecan Hydrochloride, and 5-fluorouracil.
  • the cancer is hepatocellular carcinoma and, preferably, the method of treatment can be a first line cancer treatment. In some other embodiments, the cancer is colorectal cancer.
  • the method of treatment comprises administering the bispecific antibody, e.g. at a dosage of 20 mg/kg every two weeks, in combination with oxaliplatin, calcium folinate, and 5-fluorouracil (which may also be referred to as FOLFOX4) .
  • the cancer is hepatocellular carcinoma and, preferably, the method of treatment can be a first line cancer treatment.
  • the method of treatment comprises administering the bispecific antibody in combination with irinotecan, 5-fluorouracil, calcium folinate.
  • the cancer is unresectable neuroendocrine neoplasm and, preferably, the method of treatment can be a second line cancer treatment.
  • the method of treatment comprises administering the bispecific antibody in combination with etoposide and platinum.
  • the cancer is small cell lung cancer, e.g., extensive-stage small cell lung cancer or limited-stage small cell lung cancer, and, preferably, the method of treatment can be a first line cancer treatment.
  • the method of treatment comprises administering the bispecific antibody every 3 weeks at a dosage ranging from 20 mg/kg to 30 mg/kg in combination with etoposide with carboplatin to a subject having small cell lung cancer, e.g., extensive-stage small cell lung cancer or limited-stage small cell lung cancer.
  • the method of treatment comprises administering the bispecific antibody every 3 weeks at a dosage ranging from 20 mg/kg to 30 mg/kg (preferably at 20 mg/kg or 30 mg/kg) in combination with paclitaxel, lurbinectedin, or topotecan to a subject having small cell lung cancer, e.g., extensive-stage small cell lung cancer.
  • this method of treatment is a second line treatment, in particular a treatment of SCLC patients who progressed during or after first-line platinum-based therapy (with or without checkpoint inhibitor therapy) .
  • this method of treatment comprises paclitaxel, in particular paclitaxel every 3 weeks at a dosage of 175 mg/m 2 .
  • this method of treatment comprises topotecan, in particular topotecan at a dosage of 1.5 mg/m 2 administered IV or 2.3 mg/m 2 administered orally once per day on days 1 to 5 of every three weeks cycle.
  • the method of treatment comprises administering the bispecific antibody every 3 weeks at a dosage ranging from 1400 mg to 2000 mg in combination with etoposide with carboplatin to a subject having small cell lung cancer, e.g., extensive-stage small cell lung cancer.
  • the method of treatment comprises administering the bispecific antibody every 2 weeks at a dosage ranging from 10 mg/kg to 20 mg/kg, e.g.
  • the method of treatment comprises administering the bispecific antibody at a flat dosage, e.g. at a dosage of 500 mg to 3000 mg, 750 mg to 2500 mg, 1000 mg to 2250 mg or 1500 mg to 2000 mg to a subject.
  • the bispecific antibody is administered every week or every 2, 3 or 4 weeks, preferably every 2 weeks.
  • Simulations using integrated PopPK (population pharmacokinetic) analysis surprisingly show that flat dosing and weight-based dosing approaches provide similar results.
  • a fixed dosing approach is desirable to facilitate drug preparation without the need to calculate the dosage, per participant, thus lowering the potential risk of dosing errors as compared with body weight-based dosing.
  • fixed dosing also offers several advantages over weight-based dosing including better convenience and compliance, reduction of preparation time, and a reduced amount of drug waste.
  • the method of treatment comprises administering the bispecific antibody every 2 weeks at a dosage of 500 mg to 3000 mg, 750 mg to 2500 mg, 1000 mg to 2250 mg or 1500 mg to 2000 mg to a subject, preferably of 1000 mg or 1400 mg to a subject having triple-negative breast cancer, preferably on the 1 st and 15 th day of a 28-day treatment cycle. It can be preferred to administer the bispecific antibody at a dosage of 1400 mg (preferably on the 1 st and 15 th day of a 28-days treatment cycle) or to administer the bispecific antibody at a dosage of 2000 mg (preferably on the 1 st day of a 21-days treatment cycle) to a subject having triple-negative breast cancer.
  • the bispecific antibody is administered in combination with a chemotherapy.
  • the chemotherapy is selected from the group consisting of nab-paclitaxel, paclitaxel, or gemcitabine with carboplatin.
  • the chemotherapy is nab-paclitaxel.
  • the chemotherapy is administered on the 1 st , 8 th and 15 th day of a 28-day treatment cycle.
  • the subject has not received prior systemic treatment, preferably not in the advanced setting.
  • the method of treatment comprises administering the bispecific antibody every 2 weeks at a dosage of 500 mg to 3000 mg, 750 mg to 2500 mg, 1000 mg to 2250 mg or 1500 mg to 2000 mg to a subject, preferably of 1000 mg or 1400 mg to a subject having small cell lung cancer, preferably on the 1 st day of a 21-day treatment cycle.
  • the bispecific antibody is administered in combination with a chemotherapy, preferably selected from paclitaxel, topotecan or lurbinectedin.
  • the bispecific antibody is administered in combination with a chemotherapy, preferably selected from paclitaxel or topotecan.
  • the chemotherapy is paclitaxel.
  • the paclitaxel is administered on the 1 st day of a 21-day treatment cycle.
  • the chemotherapy is topotecan.
  • the topotecan is administered on the 1 st and 5 th day of a 21-day treatment cycle.
  • the invention further provides a chemotherapy agent for use in a method of treating a subject with cancer, the method comprising administering to the subject:
  • a bispecific antibody that specifically binds to PD-L1 and VEGF
  • the subject has a PD-L1 expression score before the treatment as determined by the combined positive score (CPS) of ⁇ 1 or other integrating scoring algorithm defining a similar PD-L1 expression score.
  • CPS combined positive score
  • the embodiments disclosed herein for the method of treatment comprising the bispecific antibody in combination with the chemotherapy can be used in a method of treatment of the chemotherapy agent in combination with the bispecific antibody as disclosed herein.
  • Features described herein in more detail for the “bispecific antibody for use in a method of treating” embodiments equally apply to the chemotherapy agent for use in a method of treating disclosed herein.
  • the invention further provides a method of treating cancer in a subject, the method comprising administering to the subject a bispecific antibody that specifically binds to PD-L1 and VEGF, in combination with chemotherapy, optionally wherein the subject has a PD-L1 expression score before the treatment as determined by the combined positive score (CPS) of ⁇ 1 or other integrating scoring algorithm defining a similar PD-L1 expression score.
  • a bispecific antibody that specifically binds to PD-L1 and VEGF
  • chemotherapy optionally wherein the subject has a PD-L1 expression score before the treatment as determined by the combined positive score (CPS) of ⁇ 1 or other integrating scoring algorithm defining a similar PD-L1 expression score.
  • CPS combined positive score
  • the embodiments disclosed herein for the method of treatment comprising the bispecific antibody in combination with the chemotherapy can be used in a method of treating cancer in a subject as disclosed herein.
  • Features described herein in more detail for the “bispecific antibody for use in a method of treating” embodiments equally apply to the method of treatment disclosed herein.
  • the method is a method for extending progression-free survival in said subject compared to the chemotherapy or the bispecific antibody or an anti PD-L1 antibody or an anti-PD-1 antibody treatment alone or compared to a standard treatment comprising the chemotherapy and the anti-PD-L1 antibody or the chemotherapy and the anti-PD-1 antibody, wherein the anti-PD-L1 antibody is preferably atezolizumab and the anti-PD-L1 antibody is preferably pembrolizumab.
  • the method is a method for increased overall survival in said subject compared to the chemotherapy or the bispecific antibody or an anti PD-L1 antibody or an anti-PD-1 antibody treatment alone or compared to a standard treatment comprising the chemotherapy and the anti-PD-L1 antibody or the chemotherapy and the anti-PD-1 antibody, wherein the anti-PD-L1 antibody is preferably atezolizumab and the anti-PD-L1 antibody is preferably pembrolizumab.
  • the invention provides a bispecific antibody that specifically binds to PD-L1 and VEGF for use in a method of treating a subject with triple-negative breast cancer, the method comprising administering to the subject:
  • a chemotherapy preferably nab-paclitaxel; wherein the subject has a PD-L1 expression score before the treatment similar or identical to a CPS of ⁇ 1 to ⁇ 10 as determined by the TPS scoring algorithm.
  • the invention provides a bispecific antibody that specifically binds to PD-L1 and VEGF for use in a method of treating a subject with triple-negative breast cancer, the method comprising administering to the subject:
  • a chemotherapy preferably nab-paclitaxel
  • the subject has a PD-L1 expression score before the treatment similar or identical to a CPS of ⁇ 1 to ⁇ 10 as determined by the TAP scoring algorithm.
  • the invention provides a bispecific antibody that specifically binds to PD-L1 and VEGF for use in a method of treating a subject with triple-negative breast cancer, the method comprising administering to the subject:
  • a chemotherapy preferably nab-paclitaxel
  • CPS combined positive score
  • the invention provides a bispecific antibody that specifically binds to PD-L1 and VEGF for use in a method of treating a subject with triple-negative breast cancer, the method comprising administering to the subject:
  • a chemotherapy preferably a chemotherapy agent
  • the subject has a PD-L1 expression score before the treatment as determined by a combined positive score (CPS) of ⁇ 1 to ⁇ 10 or another integrating scoring algorithm defining a similar PD-L1 expression score, wherein the other integrating scoring algorithm is selected from tumour area positivity (TAP) score and tumour proportion score (TPS) , preferably wherein the other integrating scoring algorithm is TAP score.
  • CPS combined positive score
  • TAP tumour area positivity
  • TPS tumour proportion score
  • the invention provides a bispecific antibody that specifically binds to PD-L1 and VEGF for use in a method of treating a subject with triple-negative breast cancer, the method comprising administering to the subject:
  • a chemotherapy preferably a chemotherapy agent
  • the subject has a PD-L1 expression before the treatment that provides a score of ⁇ 1 to ⁇ 10 when determined by the combined positive score (CPS) or a score that is indicative of such a PD-L1 expression when determined by another integrating scoring algorithm, preferably when determined by the tumour area positivity (TAP) score or the tumour proportion score (TPS) , more preferably when determined by the TAP score.
  • CPS combined positive score
  • TAP tumour area positivity
  • TPS tumour proportion score
  • the invention provides a bispecific antibody that specifically binds to PD-L1 and VEGF for use in a method of treating a subject with cancer, the method comprising administering to the subject:
  • a chemotherapy preferably a chemotherapy agent
  • the subject has a PD-L1 expression before the treatment that provides a score of ⁇ 1 when determined by the combined positive score (CPS) or a score that is indicative of such a PD-L1 expression when determined by another integrating scoring algorithm, preferably when determined by the tumour area positivity (TAP) score or the tumour proportion score (TPS) , more preferably when determined by the TAP score.
  • CPS combined positive score
  • TAP tumour area positivity
  • TPS tumour proportion score
  • a bispecific antibody that specifically binds to PD-L1 and VEGF and a chemotherapy agent in the manufacture of a medicament for treating cancer in a subject, the use comprising administering to the subject:
  • a bispecific antibody that specifically binds to PD-L1 and VEGF in the manufacture of a medicament for treating cancer in a subject, the use comprising administering to the subject:
  • a bispecific antibody that specifically binds to PD-L1 and VEGF and a chemotherapy agent in the manufacture of a medicament for treating cancer in a subject, the use comprising administering to the subject:
  • a chemotherapy agent in the manufacture of a medicament for treating cancer in a subject, the use comprising administering to the subject:
  • a bispecific antibody that specifically binds to PD-L1 and VEGF
  • the invention further provides a method for determining whether a cancer in a subject is susceptible to treatment with a bispecific antibody that specifically binds to PD-L1 and VEGF and a chemotherapy, wherein the method comprises detecting in a sample of the subject a PD-L1 expression score before the treatment as determined by the combined positive score (CPS) of ⁇ 1 or other integrating scoring algorithm defining a similar PD-L1 expression score, wherein the CPS of ⁇ 1 indicates that the subject is susceptible to treatment with the bispecific antibody and the chemotherapy.
  • CPS combined positive score
  • the embodiments for determining PD-L1 expression score in cancer tissue disclosed herein for the method of treatment comprising the bispecific antibody in combination with the chemotherapy can be used in the method for determining whether a cancer in a subject is susceptible to treatment with a bispecific antibody that specifically binds to PD-L1 and VEGF and a chemotherapy.
  • a bispecific antibody that specifically binds to PD-L1 and VEGF and a chemotherapy.
  • the method for determining whether a cancer in a subject is susceptible to treatment with a bispecific antibody that specifically binds to PD-L1 and VEGF and a chemotherapy is conducted using the IHC assay PD-L1 IHC 22C3 pharmDx in accordance with the manufacturer’s guide.
  • the invention further provides kit-of-parts comprising the bispecific antibody disclosed herein that specifically binds to PD-L1 and VEGF and the chemotherapy agent disclosed herein.
  • kits-of-parts for the method of treatment comprising the bispecific antibody in combination with the chemotherapy can be used in the kit-of-parts disclosed herein.
  • the bispecific antibody for use in a method of treating embodiments equally apply to the kit-of-parts disclosed herein.
  • the bispecific antibody and the chemotherapy agent are comprised in separate container.
  • kit-of parts further comprise instructions for use.
  • the present application is directed to a bispecific antibody that specifically binds to PD-L1 and VEGF (preferably PM8002 comprising the heavy and light chain amino acid sequences as set forth in SEQ ID NOs: 16 and 17) for use in a method of treating a subject with small cell lung cancer, the method comprising administering to the subject the bispecific antibody in combination with paclitaxel, wherein the antibody is administered every three weeks at a dosage of about 20 mg/kg or about 30 mg/kg and the paclitaxel is administered every three weeks at a dosage of about 175 mg/m 2 .
  • PD-L1 and VEGF preferably PM8002 comprising the heavy and light chain amino acid sequences as set forth in SEQ ID NOs: 16 and 17
  • the patient progressed during or after first-line platinum-based therapy (with or without Immuno-oncology (IO) , e.g., checkpoint inhibitor therapy) , i.e. the patient failed first-line platinum-based chemotherapy.
  • first-line platinum-based therapy with or without Immuno-oncology (IO) , e.g., checkpoint inhibitor therapy
  • IO Immuno-oncology
  • the method of the present paragraph is a second-line treatment for a patient suffering from small cell lung cancer.
  • the combination is administered intravenously.
  • the treatment may take place for 5 cycles (3 weeks/cycle) , followed by a maintenance therapy by the antibody at a dosage of about 20 mg/kg or about 30 mg/kg every three weeks.
  • the present application is directed to a bispecific antibody that specifically binds to PD-L1 and VEGF (preferably PM8002 comprising the heavy and light chain amino acid sequences as set forth in SEQ ID NOs: 16 and 17) for use in a method of treating a subject with small cell lung cancer, the method comprising administering to the subject the bispecific antibody in combination with topotecan, e.g., wherein the antibody is administered every three weeks at a dosage of about 20 mg/kg or about 30 mg/kg and the topotecan is administered every three weeks at days 1 to 5 once daily at a dosage of about 1.5 mg/m 2 IV or about 2.3 mg/m 2 orally.
  • topotecan e.g., wherein the antibody is administered every three weeks at a dosage of about 20 mg/kg or about 30 mg/kg and the topotecan is administered every three weeks at days 1 to 5 once daily at a dosage of about 1.5 mg/m 2 IV or about 2.3 mg/m 2 orally.
  • the patient progressed during or after first-line platinum-based therapy (with or without checkpoint inhibitor therapy) , i.e. the patient failed first-line platinum-based chemotherapy.
  • the method of the present paragraph is a second-line treatment for a patient suffering from small cell lung cancer. It is also preferred that the antibody is administered intravenously.
  • systemic chemotherapy in particular with platinum-etoposide
  • the patient has not received systemic treatment for extensive-stage small cell lung cancer prior to the administration, i.e. the treatment is a first-line treatment.
  • the method of the present paragraph is a first-line treatment for a patient suffering from extensive-stage small cell lung cancer.
  • the antibody is administered intravenously. The treatment may take place for 4 cycles (3 weeks/cycle) , followed by a maintenance therapy by the antibody at a dosage of about 20 mg/kg or about 30 mg/kg every three weeks.
  • systemic chemotherapy in particular with platinum-etoposide
  • the patient had TFI ⁇ 6 months since the last chemotherapy, chemoradiotherapy or radiotherapy. It is also preferred that the antibody is administered intravenously. The treatment may take place for 4 cycles (3 weeks/cycle) , followed by a maintenance therapy by the antibody at a dosage of about 20 mg/kg or about 30 mg/kg every three weeks.
  • systemic chemotherapy in particular with platinum-etoposide
  • the patient has not received systemic treatment for extensive-stage small cell lung cancer prior to the administration, i.e. the treatment is a first-line treatment.
  • the method of the present paragraph is a first-line treatment for a patient suffering from extensive-stage small cell lung cancer.
  • the antibody is administered intravenously. The treatment may take place for 4 cycles (3 weeks/cycle) , followed by a maintenance therapy by the antibody at a dosage of about 1400 mg or about 2000 mg every three weeks.
  • the present application is directed to a bispecific antibody that specifically binds to PD-L1 and VEGF (preferably PM8002 comprising the heavy and light chain amino acid sequences as set forth in SEQ ID NOs: 16 and 17) for use in a method of treating a subject with triple negative breast cancer (TNBC) , the method comprising administering to the subject the bispecific antibody in combination with systemic chemotherapy, wherein the systemic chemotherapy is nab-paclitaxel, which can preferably be administered at a dosage of about 100 mg/m 2 on the 1 st , 8 th , and 15 th day of a 28-days treatment cycle (preferably in combination with the bispecific antibody at a dosage of about 15 mg/kg or about 20 mg/kg on the 1 st and 15 th day of a 28-days treatment cycle) ; or wherein the systemic chemotherapy is paclitaxel, which can preferably be administered at a dosage of about 90 mg/m 2 on the 1 st , 8 th ,
  • the present application is directed to a bispecific antibody that specifically binds to PD-L1 and VEGF (preferably PM8002 comprising the heavy and light chain amino acid sequences as set forth in SEQ ID NOs: 16 and 17) for use in a method of treating a subject with non-small cell lung cancer, the method comprising administering to the subject the bispecific antibody in combination with chemotherapy (in particular carboplatin and pemetrexed) , wherein the antibody is preferably administered every three weeks at a dosage of about 30 mg/kg together with the chemotherapy (in particular carboplatin and pemetrexed at a dosage of about AUC 5 mg/mL/min carboplatin and about 500 mg/m 2 pemetrexed) .
  • chemotherapy in particular carboplatin and pemetrexed
  • the patient progressed after first-line EGFR-TKI therapy, i.e. the patient failed first-line EGFR-TKI therapy.
  • the method of the present paragraph is a second-line treatment for a patient suffering from non-small cell lung cancer.
  • the patient suffers from a NSCLC with PD-L1 expressed, i.e. with a PD-L1 expression score before the treatment as determined by a CPS of ⁇ 1 or other integrating scoring algorithm defining a similar PD-L1 expression score.
  • the present application is directed to a bispecific antibody that specifically binds to PD-L1 and VEGF (preferably PM8002 comprising the heavy and light chain amino acid sequences as set forth in SEQ ID NOs: 16 and 17) for use in a method of treating a subject with non-small cell lung cancer (NSCLC) , e.g., to a patient suffering from NSCLC as second-line treatment, e.g., to a patient suffering from second-line stage IV or recurrent NSCLC or, e.g., to a patient who progressed at least one prior line of an immune-oncology (IO) -comprising treatment (such as an immune checkpoint inhibitor-comprising treatment) , wherein the method comprises administering to the subject the bispecific antibody (preferably at a dosage range of about 1400 mg to about 2000 mg [with about 1400 mg or about 2000 mg being more preferred] ) and docetaxel (preferably at about 75 mg/m 2 every three weeks) .
  • NSCLC non-
  • the bispecific antibody may be administered at a dosage of about 2000 mg bispecific antibody plus about 75 mg/m 2 docetaxel every three weeks.
  • the bispecific antibody may be administered in a step-up dosing regimen with a first and a second dose regimen, preferably wherein the first dose regimen is about 1400 mg bispecific antibody plus about 60 mg/m 2 docetaxel every three weeks or about 1400 mg bispecific antibody plus about 75 mg/m 2 docetaxel every three weeks or about 2000 mg bispecific antibody plus about 60 mg/m 2 docetaxel every three weeks and the second dose regimen is about 2000 mg bispecific antibody plus about 75 mg/m 2 docetaxel every three weeks.
  • the bispecific antibody may be administered in a step-down dosing regimen with a first and a second dose regimen, preferably wherein the first dose regimen is about 2000 mg bispecific antibody plus about 75 mg/m 2 docetaxel every three weeks and the second dose regimen is about 1400 mg bispecific antibody plus about 75 mg/m 2 docetaxel every three weeks or about 2000 mg bispecific antibody plus about 60 mg/m 2 docetaxel every three weeks.
  • Combination (i) may in particular be administered to a patient suffering from non-squamous NSCLC, whereas combination (ii) may in particular be administered to a patient suffering from squamous NSCLC, wherein the maintenance therapy may be at a dosage of about 1400 mg or about 2000 mg bispecific antibody plus pemetrexed (preferably at a dosage of about 500 mg/m 2 ) for patient (i) and a dosage of about 1400 mg or about 200 mg bispecific antibody for patient (ii) .
  • the present application is directed to a bispecific antibody that specifically binds to PD-L1 and VEGF (preferably PM8002 comprising the heavy and light chain amino acid sequences as set forth in SEQ ID NOs: 16 and 17) for use in a method of treating a subject with hepatocellular cancer, the method comprising administering to the subject the bispecific antibody in combination with chemotherapy (in particular FOLFOX4, i.e. oxaliplatin, leucovorin and 5-fluorouracil) , wherein the antibody is administered every two weeks at a dosage of about 20 mg/kg together with the chemotherapy.
  • chemotherapy in particular FOLFOX4, i.e. oxaliplatin, leucovorin and 5-fluorouracil
  • the patient has not received systemic treatment for hepatocellular cancer prior to the administration, i.e. the treatment is a first-line treatment.
  • the method of the present paragraph is a first-line treatment for a patient suffering from hepatocellular cancer.
  • the present application is directed to a bispecific antibody that specifically binds to PD-L1 and VEGF (preferably PM8002 comprising the heavy and light chain amino acid sequences as set forth in SEQ ID NOs: 16 and 17) for use in a method of treating a subject with hepatocellular cancer, the method comprising administering to the subject the bispecific antibody (preferably as the sole active agent) , wherein the antibody is administered every two weeks at a dosage of about 20 mg/kg.
  • the patient has not received systemic treatment for hepatocellular cancer prior to the administration, i.e. the treatment is a first-line treatment.
  • the method of the present paragraph is a first-line treatment for a patient suffering from hepatocellular cancer.
  • the bispecific antibody that specifically binds to PD-L1 and VEGF (most preferably PM8002 comprising the heavy and light chain amino acid sequence set forth in SEQ ID NO: 16 and 17) in combination with (i) etoposide and carboplatin; (ii) paclitaxel; (iii) topotecan; (iv) Nab-paclitaxel; (v) paclitaxel; (vi) gemcitabine; (vii) eribulin; (viii) carboplatin and pemetrexed; (ix) carboplatin and paclitaxel; or (x) docetaxel.
  • PM8002 comprising the heavy and light chain amino acid sequence set forth in SEQ ID NO: 16 and 17
  • the bispecific antibody may comprise in a general aspect an anti-VEGF antibody (e.g., an anti-VEGF-A antibody) or fragment thereof, and an antagonist of the PD1/PD-L1 interaction and/or a PD-1 or PD-L1 blocking antibody.
  • the bispecific antibody comprises an anti-VEGF antibody (e.g., an anti-VEGF-A antibody) or fragment thereof, and a PD-1 or PD-L1 blocking antibody.
  • the bispecific antibody comprises an anti-VEGF antibody (e.g., an anti-VEGF-A antibody) or fragment thereof, and an anti-PD-1 or anti-PD-L1 antibody or fragment thereof.
  • the anti-PD-1 antibody can be selected from any anti-PD-1 antibody known in the art such as pembrolizumab or nivolumab.
  • An exemplary anti-PD-L1 antibody includes atezolizumab.
  • the anti-VEGF antibody can be selected from any VEGF antibody known in the art such as bevacizumab, ranibizumab or an VEGF binding region derived from the anti-VEGF fusion protein Aflibercept (see, e.g., US 7070959) .
  • An exemplary anti-VEGF antibody includes bevacizumab.
  • FIG. 1 depicts boxplots of AUC tau, ss by 20 mg/kg Q2W (A) versus 1200 mg Q2W (B) or 1500 mg Q2W (C) dosing regimens.
  • N is the number of participants; the x-axis represents baseline body weight, the horizontal line at the center of the box is the median of AUC tau, ss , the box represents the inter-quartile distance, and the whiskers represent ⁇ 1.5 times the inter-quartile range (75th -25th quartile) .
  • the number at the top of the figure represents the number of participants included in each category.
  • SEQ ID NO: 1-3 are exemplary CDR1-3 amino acid sequences of an anti-PD-L1 antibody using the IMGT numbering system.
  • SEQ ID NO: 4-6 are exemplary HCDR1-3 amino acid sequences of an anti-VEGF antibody using the IMGT numbering system.
  • SEQ ID NO: 7 and 8 are exemplary LCDR1 and 3 amino acid sequences of an anti-VEGF antibody using the IMGT numbering system.
  • SEQ ID NO: 9 is an exemplary amino acid sequence of an anti-PD-L1 VHH.
  • SEQ ID NO: 10 is an exemplary VH amino acid sequence of an anti-VEGF antibody.
  • SEQ ID NO: 11 is an exemplary VL amino acid sequence of an anti-VEGF antibody.
  • SEQ ID NO: 12 is an exemplary CH1 amino acid sequence of an anti-VEGF antibody.
  • SEQ ID NO: 13 is an exemplary IgG1 Fc region amino acid sequence of an anti-VEGF antibody.
  • SEQ ID NO: 14 is an exemplary linker amino acid sequence of the bispecific antibody as disclosed herein.
  • SEQ ID NO: 15 is an exemplary CL amino acid sequence of an anti-VEGF antibody.
  • SEQ ID NO: 16 is an exemplary heavy chain amino acid sequence of the bispecific antibody as disclosed herein comprising an exemplary anti-PD-L1 VHH amino acid sequence.
  • SEQ ID NO: 17 is an exemplary light chain amino acid sequence of the bispecific antibody as disclosed herein.
  • SEQ ID NO: 18, 19 and 38 are exemplary CDR1-3 amino acid sequences of an anti-PD-L1 antibody using the Kabat numbering system.
  • SEQ ID NO: 20-25 are exemplary LCDR1-3 and HCDR1-3 amino acid sequences of the 22C3 antibody.
  • SEQ ID NO: 26 is an exemplary VL amino acid sequence of the 22C3 antibody.
  • SEQ ID NO: 27 is an exemplary VH amino acid sequence of the 22C3 antibody.
  • SEQ ID NO: 28 is an exemplary VH amino acid sequence of the 28-8 antibody.
  • SEQ ID NO: 29 is an exemplary VL amino acid sequence of the 28-8 antibody.
  • SEQ ID NO: 30-35 are exemplary LCDR1-3 and HCDR1-3 amino acid sequences of the SP263 antibody.
  • SEQ ID NO: 36 is an exemplary VH amino acid sequence of the SP263 antibody.
  • SEQ ID NO: 37 is an exemplary VL amino acid sequence of the SP263 antibody.
  • SEQ ID NO: 39-41 are exemplary HCDR1-3 amino acid sequences of an anti-VEGF-A antibody using the Kabat numbering system.
  • SEQ ID NO: 42 and 43 are exemplary LCDR1 and 2 amino acid sequences of an anti-VEGF-A antibody using the Kabat numbering system.
  • An exemplary anti-VEGF-A LCDR2 is the amino acid sequence FTS referred to herein as SEQ ID NO: 44 using the IGMT numbering system.
  • sequences of SEQ ID NO: 1-44 are shown in the table below.
  • Example 1 Determining the CPS of a cancer tissue sample using Dako’s PD-L1 IHC 22C3 pharmDx kit in combination with anti-PD-L1 antibody clone 22C3.
  • This example is to provide guidelines for evaluating PD-L1 expression on formalin-fixed, 20 paraffin-embedded (FFPE) tumour tissue section with Dako’s PD-L1 IHC 22C3 pharmDx kit (SK006) according to the manufacturer’s TNBC Instructions for Use.
  • This immunohistochemical (IHC) assay has been performed using the Dako Auto-stainer Link 48 automated staining system.
  • PD-L1 IHC 22C3 pharmDx kit which is a qualitative immunohistochemical assay using Monoclonal Mouse Anti-PD-L1, Clone 22C3.
  • This kit is intended for use in the detection of PD-L1 protein in formalin-fixed, paraffm-30 embedded (FFPE) tumour tissue using EnVision FLEX visualization system on Autostainer Link 48.
  • FFPE formalin-fixed, paraffm-30 embedded
  • PD-L1 protein expression was used to determine a Combined Positive Score (CPS) .
  • CPS Combined Positive Score
  • PD-L1 IHC 22C3 pharmDx contains optimized reagents to perform an IHC staining procedure using a linker and a chromogen enhancement reagent. Deparaffinization, rehydration, and target retrieval was performed using a 3-in-1 procedure on PT Link.
  • specimens were incubated with the monoclonal mouse primary antibody to PD-L1 or the Negative Control Reagent. Specimens were then incubated with a Mouse LINKER, followed by incubation with a ready-to-use Visualization Reagent consisting of secondary antibody molecules and horseradish peroxidase molecules coupled to a dextran polymer backbone. The enzymatic conversion of the subsequently added chromogen resulted in precipitation of a visible reaction product at the site of the antigen. The color of the chromogenic reaction was modified by a chromogen enhancement reagent. The specimen was counterstained and coverslipped and results were interpreted using a light microscope.
  • hematoxylin and eosin (H&E) stain of the tissue specimen were evaluated first to assess tissue histology and preservation quality.
  • PD-L1 IHC 22C3 pharmDx and the H&E staining were performed on serial sections from the same paraffin block of the specimen (sample) . Tissue specimens were intact, well preserved, and confirmed tumour indication.
  • the specimen contained a minimum of 100 viable tumour cells to determine the percentage of positive cells.
  • tissue from a deeper level of the block, or potentially another block presented sufficient number of viable tumour cells for PD-L1 IHC 22C3 pharmDx testing.
  • the PD-L1 IHC 22C3 pharmDx Control Cell Line Slide were examined to determine that reagents are functioning properly. Each slide contained sections of cell pellets with positive and negative PD-L1 expression. The percentage of positive cells, staining intensity, and non-specific staining were assessed in both cell pellets. If any staining of the Control Cell Line Slide was not satisfactory, all results with the subject specimens were considered invalid. The Control Cell Line Slide has not been used as an aid in interpretation of subject results.
  • the overall staining intensity was evaluated using the following guide:
  • Non-specific staining ⁇ 1+ intensity Note that staining of a few cells in the MCF-7 cell pellet may occasionally be observed. The following acceptance criteria are applicable: the presence of ⁇ 10 total cells with distinct plasma membrane staining, or cytoplasmic staining with ⁇ 1+ intensity within the boundaries of the MCF-7 cell pellet are acceptable
  • TNBC Positive and Negative User Control Tissue
  • the TNBC Positive Control Tissue Slides were examined to verify that the fixation method and epitope retrieval process are effective.
  • the Positive Control Tissue Slides were stained with both PD-L1 primary antibody and Negative Control Reagent.
  • the ideal positive control tissue provided a complete dynamic representation of weak-to-moderate staining of tumour cells and tumour-associated mononuclear inflammatory cells (MICs) .
  • MICs mononuclear inflammatory cells
  • Known positive tissue controls were utilized for monitoring the correct performance of processed tissues and test reagents, not as an aid in formulating a specific diagnosis of subject samples. If stainings of positive in-house control tissue were not satisfactory, all results with the subject specimen were considered invalid.
  • Tonsil stained with PD-L1 exhibited strong membrane staining in portions of the crypt epithelium and weak-to-moderate membrane staining of the follicular macrophages in the germinal centers.
  • Negative Control Reagent NCR
  • the slides stained with the NCR were examined to identify non-specific background staining that may interfere with PD-L1 staining interpretation, making the specimen non-evaluable. Satisfactory performance was indicated by 0 specific staining and ⁇ 1+ non-specific staining.
  • the subject specimens stained were examined with the NCR to determine if there is any non-specific staining that may interfere with interpreting the PD-L1 stained slide.
  • Non-specific staining was ⁇ 1+.
  • NCR-stained slides indicated non-specific background staining and allowed for better interpretation of subject specimens stained with the primary antibody.
  • PD-L1 expression score in TNBC was determined by using combined positive score (CPS) , which is the number of PD-L1 staining cells (tumour cells, lymphocytes, macrophages) divided by the total number of viable tumour cells, multiplied by 100. Although the result of the calculation can exceed 100, the maximum score was defined as CPS 100.
  • CPS combined positive score
  • tissue from a deeper level of the block or potentially another block has a sufficient number of tumour cells for evaluation of PD-L1 expression
  • the number of PD-L1 staining cells was determined (tumour cells, lymphocytes, macrophages) (CPS numerator; see Tables 1 and 2 for additional CPS inclusion/exclusion criteria)
  • membrane and cytoplasmic staining can be indistinguishable due to high nuclear to cytoplasmic ratio. Therefore, membrane and/or cytoplasmic staining of MICs was included in the score.
  • Adjacent MICs were defined as being within the same 20 ⁇ field as the tumour. However, MICs that were NOT directly associated with the response against the tumour were excluded.
  • Macrophages and histiocytes have been considered the same cells.
  • Example 2 Determining the CPS of a cancer tissue sample using PD-L1 IVD Kit (MEDx Inc. ) in combination with anti-PD-L1 antibody clone E1L3N.
  • the PD-L1 expression score was determined using the PD-L1 IVD Kit (MEDx Inc. ) and clone E1L3N according to the Manufacturer’s Instructions for Use. CPS definition and scoring process has been conducted according to a similar method as the PD-L1 IHC 22C3 pharmDx’s Instructions for Use described in example 1.
  • Example 3 Efficacy of a First-Line therapy of a bispecific anti VEGF-A anti PD-L1 antibody (PM8002) in Combination with Chemotherapy for Subjects with Triple-Negative Breast Cancers (TNBC)
  • PM8002 comprising the heavy and light chain amino acid sequence set forth in SEQ ID NO: 16 and 17
  • TNBC tention-to-treat population
  • ER ER
  • PR HER-2
  • Negative ER and PR are defined as: IHCER ⁇ 1%, IHCPR ⁇ 1%.
  • HER-2 negative is defined as: IHCHER-2 (-) or (1+) , HER-2 (2+) must be tested by FISH and the result is negative.
  • Study arm PM8002 at 20 mg/kg (Q2W) and nab-paclitaxel at 100 mg/m 2 on the 1st, 8th, and 15th days of each cycle until unacceptable toxicity or disease progression were observed. Each cycle contains 28 days.
  • ORR Objective Response Rate
  • TREEs Treatment-Related Adverse Events
  • ORR is the proportion of subjects with complete response (CR) or partial response (PR) , based on RECIST v1.1.
  • the secondary endpoint of the study was the Progression-free survival (PFS) and the Disease Control rate (DCR) based on Investigator assessments per RECIST v1.1.
  • the study population included subjects aged 18 to 75 (including boundary value) . Each subject met all of the inclusion criteria and none of the exclusion criteria for this study in order to be randomized to a study intervention.
  • Subjects who have not received prior systemic treatment for advanced TNBC are eligible for the study.
  • Subjects who have received taxane-based chemotherapy or pembrolizumab during the neoadjuvant and/or adjuvant treatment phase are eligible if the occurrence of relapse or metastasis was more than 12 months after the end of such treatment (s) .
  • Subjects should provide a fresh tumour biopsy during the screening period (bone biopsies, fine-needle aspiration biopsies, and samples from pleural or peritoneal fluid are not acceptable, subjects with only one target lesion are not eligible to provide biopsy) .
  • Sufficient qualified tumour tissue specimens should be obtained for biomarker analysis including PD-L1 expression levels. If a subject is unable to provide a fresh biopsy, a recent tumour sample (up to a maximum of 24 months prior to the start of the study) processed through formalin-fixed paraffin embedding (FFPE) or unstained slides (3-5 ⁇ m) is acceptable for the corresponding biomarker analysis. If a subject is unable to provide specimens that meet the aforementioned requirements, she/he may still participate in the screening process with the consent of the Sponsor.
  • FFPE formalin-fixed paraffin embedding
  • ANC Neutrophil count
  • PHT Platelet count
  • TBIL Total bilirubin
  • UPN upper limit of normal
  • AST Aspartate aminotransferase
  • ALT alanine aminotransferase
  • Serum creatinine ⁇ 1.5 ⁇ ULN or Creatinine Clearance (CrCl) ⁇ 50 ml/min ⁇ Cockcroft-Gault formula: [ (140 -age) ⁇ weight (kg) ⁇ (0.85, for women only) ] / [72 ⁇ creatinine (mg/dL) ] (conversion of creatinine unit: 1 mg/dL 88.4 ⁇ mol/L) ⁇ .
  • Coagulation function International normalized ratio (INR) ⁇ 1.5, activated partial thromboplastin time (APTT) ⁇ 1.5 ⁇ ULN, objects with liver metastasis INR and APTT ⁇ 2 ⁇ ULN.
  • the subject has at least 1 measurable lesion as the targeted lesion (ameasurable lesion at the previously irradiated radiation field or other local treatment area should not be selected as targeted lesion, the only bone metastasis or the only central nervous system metastasis should not be considered as a measurable lesion) .
  • Female subjects of childbearing potential have a negative blood pregnancy test result within 7 days prior to the study treatment and are willing to follow medically approved highly effective contraceptive measures (such as intrauterine device and condom) from signing the informed consent form to until 6 months after the last dosage of treatment.
  • highly effective contraceptive measures such as intrauterine device and condom
  • Adverse events resulting from prior anti-tumour therapies should be assessed and graded according to the CTCAE 5.0 criteria, subjects whose AEs have not returned to Grade 1 or below (unless the investigator determines that the current AEs pose no safety risk to the patients, such as hair loss or stable hypothyroidism under hormone replacement therapy) are not eligible for the study.
  • corticosteroids excluding local, intranasal, intraocular, intra-articular or inhaled corticosteroids, short-term use ( ⁇ 7 days) of corticosteroids for prophylaxis (e.g., prevention of contrast agent allergy) or treatment of non-autoimmune conditions (e.g., delayed hypersensitivity reactions caused by exposure to allergens) .
  • prophylaxis e.g., prevention of contrast agent allergy
  • non-autoimmune conditions e.g., delayed hypersensitivity reactions caused by exposure to allergens
  • Acute coronary syndrome CAD
  • coronary artery bypass grafting CAD
  • congestive heart failure CHF
  • aortic dissection stroke, or other grade 3 and above cardiovascular and cerebrovascular events.
  • NYHA New York Heart Association
  • LVEF left ventricular ejection fraction
  • tumour-related pain requiring analgesic treatment should have a stable analgesic regimen at screening.
  • analgesic regimen for asymptomatic metastatic lesion, if its growth may cause dysfunction or intractable pain (e.g., current epidural metastasis unrelated to spinal cord compression) , local treatment should be considered before screening, if appropriate.
  • tumour lesions With tumour lesions invading large blood vessels and are at significant risk of bleeding.
  • antiplatelet drugs including but not limited to aspirin ( ⁇ 100 mg/day) , clopidogrel (> 75 mg/day) , dipyridamole, ticlopidine or cilostazol, within 10 days prior to the study treatment, or those requiring long-term antiplatelet therapy.
  • HIV human immunodeficiency virus
  • AIDS acquired immunodeficiency syndrome
  • Subject may increase the risk of research treatment or complicate the interpretation of toxicities and adverse events, as judged by the investigator.
  • the CPS of each patient has been determined as described in example 2 using the anti-PD-L1 antibody clone E1L3N and the PD-L1 IVD Kit (MEDx Inc. ) .
  • the combination treatment disclosed herein has a beneficial effect in PD-L1 low expressing cancers (CPS subgroup ⁇ 1) similar to PD-L1 high expressing cancers (CPS subgroup ⁇ 10) .
  • the ORR in the ITT population was 78.6%, including 1 complete response and 32 partial responses, the confirmed ORR was 73.8%with the disease control rate of 95.2%.
  • the ORR in the CPS ⁇ 1 population was 76.9%, including 10 partial responses, the confirmed ORR was 76.9%with the disease control rate of 100%.
  • the ORR in the CPS ⁇ 10 population was 100%, including 9 partial responses, the confirmed ORR was 100%with the disease control rate of 100%.
  • the ORR in the CPS ⁇ 1 population was 80.0%, the confirmed ORR was 72.0%.
  • the ORR in the CPS ⁇ 1 population was 76.9%, the confirmed ORR was 76.2%. with the disease control rate of 100%.
  • Patients were continued to be treated after obtaining the results discussed above and shown below in Tables 4 and 5, and, as of 5 July 2024, the median PFS for the ITT population was 13.5 months (compared to 9.2 months as shown in Table 4) , the median time to response was 1.9 months, and the median duration of response was 11.7 months.
  • the ORR in the ITT population 1 ⁇ CPS ⁇ 10 was 68.8%, including 1 complete response and 10 partial responses, the confirmed ORR was 56.3%with the disease control rate of 93.8%.
  • the combination therapy disclosed herein shows an improved median progression-free survival compared to the standard treatment involving chemotherapy alone or chemotherapy in combination with the anti-PD-L1 antibody pembrolizumab as shown in table 5.
  • Table 5 Comparison of the current treatment of care for triple-negative breast cancer with the combination therapy disclosed herein
  • the combination therapy of the bispecific antibody targeting specifically PD-L1 and VEGF-A combined with chemotherapy showed encouraging anti-tumour activity regardless of PD-L1 status and good safety profile as a first-line therapy for TNBC cancer having a low CPS of ⁇ 1.
  • the combination therapy therefore meets the high unmet need for a breakthrough therapy designation for subject afflicted with cancer and having a low CPS of ⁇ 1.
  • the patients of the present study were also classified according to the Fudan University Shanghai Cancer Center (FUSCC) classification (see Jiang YZ, Ma D, Suo C, et al. Genomic and transcriptomic landscape of triple-negative breast cancers: subtypes and treatment strategies. Cancer Cell. 2019; 35 (3) : 428-440. e5) , which classifies TNBCs into four transcriptome-based subtypes with distinct molecular features: (1) luminal androgen receptor (LAR) , (2) immunomodulatory (IM) , (3) basal-like immune-suppressed (BLIS) , and (4) mesenchymal-like (MES) . 31 of the 42 patients could be classified according to these four transcriptome-based subtypes, and the results were as shown in Table 6.
  • FUSCC Fudan University Shanghai Cancer Center
  • ORR objective response rate
  • cORR confirmed ORR
  • disease control rate DCR
  • basal-like immune-suppressed BLIS
  • immunomodulatory IM
  • luminal androgen receptor LAR
  • mesenchymal-like MES.
  • TRAEs treatment-related adverse events
  • the present example is a Phase II study of a bispecific anti-VEGF-A anti-PD-L1 antibody (i.e., PM8002 comprising the heavy and light chain amino acid sequence set forth in SEQ ID NO: 16 and 17) in combination with paclitaxel as a second-line therapy for patients suffering from small cell lung cancer (SCLC) to assess the safety and efficacy of this treatment.
  • a bispecific anti-VEGF-A anti-PD-L1 antibody i.e., PM8002 comprising the heavy and light chain amino acid sequence set forth in SEQ ID NO: 16 and 17
  • SCLC small cell lung cancer
  • ORR objective response rate
  • PFS progression free survival
  • OS overall survival
  • results As of April 12, 2024, 60 patients have been enrolled. Among 26 patients, 22 patients completed at least one tumor assessment. 5 patients were still on treatment. Median PFS was 5.9 months and median OS was 14.4 months, which were still maturing. The ORR was 72.7% (16/22) with a disease control rate (DCR) of 81.8% (18/22) , and the median duration of response (DOR) was 11.5 months. Among 34 immunotherapy-treated patients, 29 patients completed at least one tumor assessment. 12 patients were still on treatment. The median PFS was 6.2 months which was still maturing. The ORR was 44.8% (13/29) with a DCR of 89.7% (26/29) .
  • DCR disease control rate
  • DOR median duration of response
  • Any-grade treatment-related adverse events occurred in 95% (57/60) of patients.
  • Grade ⁇ 3 TEAEs related to the combination regimen occurred in 70% (42/60) of patients, with the most common grade ⁇ 3 TRAEs observed being neutropenia (56.7%, 34/60) and leukopenia (31.7%, 19/60) .
  • Three patients discontinued PM8002 and/or paclitaxel administration due to TRAEs.
  • Any-grade immune-related adverse events occurred in 30% (18/60) of patients, and grade ⁇ 3 irAEs occurred in 3.3% (2/60) of patients.
  • the present example is an open label, single arm, multicenter Phase II study of a bispecific anti-VEGF-A anti-PD-L1 antibody (i.e., PM8002 comprising the heavy and light chain amino acid sequence set forth in SEQ ID NO: 16 and 17) in combination with systemic chemotherapy (in particular platinum-etoposide) as a first-line therapy for patients suffering from extensive-stage small cell lung cancer (ES-SCLC) to assess the safety and efficacy of this treatment.
  • systemic chemotherapy in particular platinum-etoposide
  • ES-SCLC Patients with ES-SCLC have a poor prognosis and there is an unmet medical need for such patients.
  • ECOG PS Eastern Cooperative Oncology Group Performance Status
  • ORR objective response rate
  • PFS progression free survival
  • OS overall survival
  • TRAEs Treatment-related adverse events
  • Grade ⁇ 3 TRAEs occurred in 42 patients (84%) .
  • the most commonly observed AE at any Grade was neutrophil count decrease (90%, 45/50) , white blood cell count decrease (76%, 38/50) , and platelet count decrease (60%, 30/50) .
  • Immune-related adverse events (irAEs) occurred in 34%of patients (17/50) with 4% (2/50) Grade ⁇ 3. Two patients (4%) discontinued treatment due to TRAEs.
  • the present example is a Phase II study of a bispecific anti-VEGF-A anti-PD-L1 antibody (i.e., PM8002 comprising the heavy and light chain amino acid sequence set forth in SEQ ID NO: 16 and 17) in combination with chemotherapy (in particular carboplatin and pemetrexed) as a therapy for patients suffering from EGFR-mutated NSCLC who progressed after EGFR-tyrosine kinase inhibitors (TKIs) treatment to assess the safety and efficacy of this treatment. Furthermore, the correlation between tumor PD-L1 expression and clinical response was investigated.
  • chemotherapy in particular carboplatin and pemetrexed
  • PD-L1 expression was determined by immunohistochemistry (IHC; using TPS) from patients (biopsy at baseline) after progression from EGFR-TKI therapy as disclosed above in Example 2. Patients were divided into 3 groups based on these TPS results ( ⁇ 1%defined as negative, 1 to 49%defined as low expression, and ⁇ 50%defined as high expression, using clone E1L3N as the detection antibody) .
  • the primary endpoint of this study was the objective response rate (ORR) assessed by investigators according to per RECIST v1.1.
  • PM8002 in combination with chemotherapy showed encouraging antitumor activity and acceptable tolerability in EGFR-mutated NSCLC patients that progressed after prior EGFR-TKI therapy.
  • the anti-tumor activity of PM8002 therapy is positively correlated with tumor PD-L1 expression level.
  • Example 7 Safety and Efficacy of PM8002 (anti-PD-L1 x VEGF-A bispecific) as a Single Agent or Combined with Chemotherapy for the treatment of Hepatocellular Carcinoma (HCC)
  • the present example is a Phase I/IIa study of a bispecific anti-VEGF-A anti-PD-L1 antibody (i.e., PM8002 comprising the heavy and light chain amino acid sequence set forth in SEQ ID NO: 16 and 17) as a single agent for treating HCC. Furthermore, the present example is a Phase II study of a bispecific anti-VEGF-A anti-PD-L1 antibody (i.e., PM8002 comprising the heavy and light chain amino acid sequence set forth in SEQ ID NO: 16 and 17) in combination with chemotherapy (in particular FOLFOX4 [oxaliplatin, leucovorin (which may also be referred to as calcium folinate) and 5-fluorouracil] ) for treating HCC. Both studies assessed the safety and efficacy of the respective treatments as first-line treatments for HCC.
  • chemotherapy in particular FOLFOX4 [oxaliplatin, leucovorin (which may also be referred to as calcium folinate) and 5-fluorouracil]
  • results As of April 15, 2024, a total of 46 patients participated in the two studies. 11 patients received at least one dose of PM8002 monotherapy, while 35 patients received at least one dose of the combination therapy. Two patients did not undergo tumor assessment. The ORR for the monotherapy was 27.3%, and 39.4%for the combination therapy. The disease control rates were 100%and 90.9%, respectively. The median progression-free survival was 15.1 months for the monotherapy and 5.8 months for the combination therapy. The median overall survival was 15.4 months for the combination therapy study and not reached for the monotherapy study.

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Abstract

L'invention concerne un anticorps bispécifique qui se lie spécifiquement au ligand de mort programmée 1 (PD-L1) et au facteur de croissance endothéliale vasculaire (VEGF) destiné à être utilisé dans le traitement d'un sujet atteint d'un cancer, le sujet se voyant administrer une combinaison comprenant l'anticorps bispécifique et une chimiothérapie, le sujet ayant éventuellement un score d'expression de PD-L1 avant le traitement tel que déterminé par un score positif combiné (CPS) ≥ 1 ou un autre algorithme de notation d'intégration définissant un score d'expression de PD-L1 similaire.
PCT/CN2024/124994 2024-03-07 2024-10-15 Polythérapie comprenant un anticorps bispécifique anti-vegf-a et anti-pd-l1 et une chimiothérapie pour le traitement du cancer Pending WO2025185161A1 (fr)

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PCT/CN2025/081278 WO2025185733A1 (fr) 2024-03-07 2025-03-07 Polythérapie comprenant un agent de liaison pd-1/pd-l1 et vegf/vegfr et une chimiothérapie pour le traitement du cancer

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PCT/CN2024/080506 WO2025184858A1 (fr) 2024-03-07 2024-03-07 Polythérapie comprenant un anticorps bispécifique anti-vegf-a et anti-pd-l1 et une chimiothérapie pour le traitement du cancer
CNPCT/CN2024/080506 2024-03-07
CN2024096438 2024-05-30
CN2024096309 2024-05-30
CNPCT/CN2024/096309 2024-05-30
CNPCT/CN2024/096438 2024-05-30
CNPCT/CN2024/112562 2024-08-16
CN2024112562 2024-08-16
ARP240102655A AR134001A1 (es) 2024-03-07 2024-09-30 Tratamiento conjunto que comprende un anticuerpo anti-vegf-a y anti-pd-l1 biespecífico, y una quimioterapia para el tratamiento contra cáncer
ARP20240102655 2024-09-30

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