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WO2023186067A1 - Polythérapies comprenant un conjugué anticorps anti-her2-médicament pour le traitement du cancer - Google Patents

Polythérapies comprenant un conjugué anticorps anti-her2-médicament pour le traitement du cancer Download PDF

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Publication number
WO2023186067A1
WO2023186067A1 PCT/CN2023/085380 CN2023085380W WO2023186067A1 WO 2023186067 A1 WO2023186067 A1 WO 2023186067A1 CN 2023085380 W CN2023085380 W CN 2023085380W WO 2023186067 A1 WO2023186067 A1 WO 2023186067A1
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Prior art keywords
antibody
seq
cancer
tumor
her2
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Inventor
Yanni Zhang
Yu PANG
Ke Xu
Ao LI
Zhengyi WANG
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I Mab Biopharma Co Ltd
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I Mab Biopharma Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68037—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a camptothecin [CPT] or derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6855—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
    • 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
    • C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes

Definitions

  • the present application relates to combination therapies for the treatment of cancer, which combinations comprise an anti-HER2 antibody-drug conjugate (ADC) and an agent that blocks the interaction between CD47 (e.g., hCD47) and SIRP ⁇ (e.g., SIRP ⁇ ) .
  • ADC anti-HER2 antibody-drug conjugate
  • SIRP ⁇ e.g., SIRP ⁇
  • Human epidermal growth factor receptor 2 also known as receptor tyrosine-protein kinase erbB-2, cluster of differentiation 340 (CD340) , or proto-oncogene Neu, is a protein encoded by the ERBB2 gene.
  • HER2 Human epidermal growth factor receptor 2
  • CD340 cluster of differentiation 340
  • proto-oncogene Neu is a protein encoded by the ERBB2 gene.
  • Overexpression of human HER2 occurs in ⁇ 16%of breast cancers in the United States and has been associated with a number of adverse prognostic factors.
  • HER2 overexpression has also been associated with other cancers, including, e.g., non-small cell lung cancer, gastric cancer, prostate cancer, ovarian cancer, colon cancer, bladder cancer, esophageal cancer, and head and neck cancer.
  • HER2-targeted therapeutics include therapeutic anti-HER2 antibodies and anti-HER2 antibody-drug conjugates.
  • resistance to these drugs unfortunately occurs due to a variety of mechanisms, e.g., loss of antigen expression, defects in internalization and trafficking pathways, impaired lysosomal function, and others. Poor prognosis has also been observed in patients with HER2 moderate or low expression after treatment of the HER2-targeted therapeutics.
  • a method of treating tumor in a subject comprising administering to the subject an effective amount of an agent that blocks the interaction between CD47 and SIRP ⁇ and an effective amount of an anti-HER2 antibody-drug conjugate (ADC) .
  • ADC anti-HER2 antibody-drug conjugate
  • the agent that blocks the interaction between CD47 and SIRP ⁇ is an anti-CD47 antibody or an immunologically active fragment thereof.
  • the anti-CD47 antibody or immunologically active fragment thereof is selected from the group consisting of CC-90002, 5F9, LQ001, HLX24, TI-061, AO-176, SRF-231, IBI-188, IMC-002, SHR-1603, STI-6643, ZL-1201, or an immunologically active fragment of any one of the preceding.
  • the anti-CD47 antibody or immunologically active fragment thereof comprises three complementarity determining regions (CDRs) of a heavy chain variable domain (V H ) set forth in SEQ ID NO: 1 and three CDRs of a light chain variable domain (V L ) set forth in SEQ ID NO: 2.
  • CDRs complementarity determining regions
  • the anti-CD47 antibody or immunologically active fragment thereof comprises: (a) a V H that comprises (1) a CDR-H1 comprising RAWMN (SEQ ID NO: 5) ; (2) a CDR-H2 comprising RIKRKTDGETTDYAAPVKG (SEQ ID NO: 6) ; and (3) a CDR-H3 comprising SNRAFDI (SEQ ID NO: 7) and (b) a V L that comprises (1) a CDR-L1 comprising KSSQSVLYAGNNRNYLA (SEQ ID NO: 8) ; (2) a CDR-L2 comprising QASTRAS (SEQ ID NO: 9) ; and (3) a CDR-L3 comprising QQYYTPPLA (SEQ ID NO: 10) , wherein the CDR sequences are defined according to the Kabat numbering system.
  • the V H domain of the anti-CD47 antibody or immunologically active fragment thereof comprises an amino acid sequence that has at least 95%identity to SEQ ID NO: 1
  • the V L of the anti-CD47 antibody or immunologically active fragment thereof comprises an amino acid sequence that has at least 95%identity to SEQ ID NO: 2.
  • the anti-CD47 antibody is a full length antibody.
  • the full length anti-CD47 antibody comprises a human IgG4 Fc region or a variant thereof that comprises an S228P substitution, wherein the amino acid numbering is according to the EU index.
  • the full length anti-CD47 antibody comprises a heavy chain that comprises SEQ ID NO: 3 or SEQ ID NO: 35 and a light chain that comprises SEQ ID NO: 4.
  • the anti-HER2 ADC is trastuzumab emtansine (Kadcyla) , trastuzumab deruxtecan (DS8201) , or disitamab vedotin.
  • the tumor expresses HER2. In some embodiments, the tumor expresses HER2 at a level of HER2 1+, HER2 2+ or HER2 3+ as determined by immunohistochemistry (IHC) . In some embodiments, the tumor expresses HER2 at a level of 2+or lower as determined by IHC. In some embodiments, the tumor has amplified HER2 gene as evaluated by fluorescent in situ hybridization (FISH) . In some embodiments, the tumor does not have amplified HER2 gene as evaluated by FISH. In some embodiments, the tumor expresses CD47.
  • FISH fluorescent in situ hybridization
  • the tumor expresses CD47 at a level of CD47 1+, CD47 2+ or CD47 3+ as determined by immunohistochemistry (IHC) . In some embodiments, the tumor expresses CD47 at a level of 2+ or lower as determined by IHC. In some embodiments, the IHC assay is performed using a commercially available anti-CD47 antibody.
  • the tumor is solid tumor.
  • the tumor is selected from the group consisting of lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, cholangiocarcinoma, liver cancer, cervical cancer, endometrial cancer, ovarian cancer, peritoneal cancer, urothelial cancer, bladder cancer, gastric cancer, thyroid cancer, melanoma, breast cancer, head and neck cancer, multiple myeloma, acute myeloid leukemia (AML) , uterine cancer, gastro-esophageal cancer, and rectal adenocarcinoma.
  • lung cancer colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, cholangiocarcinoma, liver cancer, cervical cancer, endometrial cancer, ovarian cancer, peritoneal cancer, urothelial cancer, bladder cancer, gastric cancer, thyroid cancer, melanoma, breast cancer, head and neck cancer,
  • the agent that blocks the interaction between CD47 and SIRP ⁇ and the anti-HER2 ADC are administered simultaneously. In some embodiments, the agent that blocks the interaction between CD47 and SIRP ⁇ and the anti-HER2 ADC are administered sequentially. In some embodiments, the agent that blocks the interaction between CD47 and SIRP ⁇ is administered prior to the anti-HER2 ADC. In some embodiments, the anti-HER2 ADC is administered prior to the agent that blocks the interaction between CD47 and SIRP ⁇ .
  • kits for treating tumor in a human subject comprising: (a) an agent that blocks the interaction between CD47 and SIRP ⁇ , and (b) instructions for administering an effective amount of the agent and an effective amount of an anti-HER2 antibody-drug conjugate (ADC) to the subject.
  • ADC anti-HER2 antibody-drug conjugate
  • the agent that blocks the interaction between CD47 and SIRP ⁇ is an anti-CD47 antibody or an immunologically active fragment thereof.
  • the anti-CD47 antibody or immunologically active fragment thereof selected from the group consisting of CC-90002, 5F9, LQ001, HLX24, TI-061, AO-176, SRF-231, IBI-188, IMC-002, SHR-1603, STI-6643, ZL-1201, or an immunologically active fragment of any one of the preceding.
  • the anti-CD47 antibody or immunologically active fragment thereof comprises three complementarity determining regions (CDRs) of a heavy chain variable domain (V H ) set forth in SEQ ID NO: 1 and three CDRs of a light chain variable domain (V L ) set forth in SEQ ID NO: 2.
  • CDRs complementarity determining regions
  • the anti-CD47 antibody or immunologically active fragment thereof comprises: (a) a V H that comprises (1) a CDR-H1 comprising RAWMN (SEQ ID NO: 5) ; (2) a CDR-H2 comprising RIKRKTDGETTDYAAPVKG (SEQ ID NO: 6) ; and (3) a CDR-H3 comprising SNRAFDI (SEQ ID NO: 7) and (b) a V L that comprises (1) a CDR-L1 comprising KSSQSVLYAGNNRNYLA (SEQ ID NO: 8) ; (2) a CDR-L2 comprising QASTRAS (SEQ ID NO: 9) ; and (3) a CDR-L3 comprising QQYYTPPLA (SEQ ID NO: 10) , wherein the CDR sequences are defined according to the Kabat numbering system.
  • the V H domain of the anti-CD47 antibody or immunologically active fragment thereof comprises an amino acid sequence that has at least 95%identity to SEQ ID NO: 1
  • the V L of the anti-CD47 antibody or immunologically active fragment thereof comprises an amino acid sequence that has at least 95%identity to SEQ ID NO: 2.
  • the anti-CD47 antibody comprises a heavy chain that comprises SEQ ID NO: 3 or SEQ ID NO: 35 and a light chain that comprises SEQ ID NO: 4.
  • the kit further comprises the anti-HER2 ADC.
  • the anti-HER2 ADC is trastuzumab emtansine (Kadcyla) , trastuzumab deruxtecan (DS8201) , or disitamab vedotin (RC48) .
  • composition comprising an agent that blocks the interaction between CD47 and SIRP ⁇ and an effective amount of an anti-HER2 antibody-drug conjugate (ADC) .
  • ADC anti-HER2 antibody-drug conjugate
  • the agent that blocks the interaction between CD47 and SIRP ⁇ is an anti-CD47 antibody or an immunologically active fragment thereof.
  • the anti-CD47 antibody or immunologically active fragment thereof is selected from the group consisting of CC-90002, 5F9, LQ001, HLX24, TI-061, AO-176, SRF-231, IBI-188, IMC-002, SHR-1603, STI-6643, ZL-1201, or an immunologically active fragment of any one of the preceding.
  • the anti-CD47 antibody or immunologically active fragment thereof comprises three complementarity determining regions (CDRs) of a heavy chain variable domain (V H ) set forth in SEQ ID NO: 1 and three CDRs of a light chain variable domain (V L ) set forth in SEQ ID NO: 2.
  • CDRs complementarity determining regions
  • the anti-CD47 antibody or immunologically active fragment thereof comprises: (a) a V H that comprises (1) a CDR-H1 comprising RAWMN (SEQ ID NO: 5) ; (2) a CDR-H2 comprising RIKRKTDGETTDYAAPVKG (SEQ ID NO: 6) ; and (3) a CDR-H3 comprising SNRAFDI (SEQ ID NO: 7) and (b) a V L that comprises (1) a CDR-L1 comprising KSSQSVLYAGNNRNYLA (SEQ ID NO: 8) ; (2) a CDR-L2 comprising QASTRAS (SEQ ID NO: 9) ; and (3) a CDR-L3 comprising QQYYTPPLA (SEQ ID NO: 10) , wherein the CDR sequences are defined according to the Kabat numbering system.
  • the V H domain of the anti-CD47 antibody or immunologically active fragment thereof comprises an amino acid sequence that has at least 95%identity to SEQ ID NO: 1
  • the V L of the anti-CD47 antibody or immunologically active fragment thereof comprises an amino acid sequence that has at least 95%identity to SEQ ID NO: 2.
  • the anti-CD47 antibody is a full length antibody.
  • the full length anti-CD47 antibody comprises a human IgG4 Fc region or a variant thereof that comprises an S228P substitution, wherein the amino acid numbering is according to the EU index.
  • the full length anti-CD47 antibody comprises a heavy chain that comprises SEQ ID NO: 3 or SEQ ID NO: 35 and a light chain that comprises SEQ ID NO: 4.
  • the anti-HER2 ADC is trastuzumab emtansine (Kadcyla) , trastuzumab deruxtecan (DS8201) , or disitamab vedotin.
  • the tumor expresses HER2. In some embodiments, the tumor expresses HER2 at a level of HER2 1+, HER2 2+ or HER2 3+ as determined by immunohistochemistry (IHC) . In some embodiments, the tumor expresses HER2 at a level of 2+ or lower as determined by IHC. In some embodiments, the tumor has amplified HER2 gene as evaluated by fluorescent in situ hybridization (FISH) . In some embodiments, the tumor does not have amplified HER2 gene as evaluated by FISH. In some embodiments, the tumor expresses CD47. In some embodiments, the tumor expresses CD47.
  • FISH fluorescent in situ hybridization
  • the tumor expresses CD47 at a level of CD47 1+, CD47 2+ or CD47 3+ as determined by immunohistochemistry (IHC) . In some embodiments, the tumor expresses CD47 at a level of 2+ or lower as determined by IHC. In some embodiments, the IHC assay is performed using a commercially available anti-CD47 antibody.
  • the tumor is solid tumor.
  • the tumor is selected from the group consisting of lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, cholangiocarcinoma, liver cancer, cervical cancer, endometrial cancer, ovarian cancer, peritoneal cancer, urothelial cancer, bladder cancer, gastric cancer, thyroid cancer, melanoma, breast cancer, head and neck cancer, multiple myeloma, acute myeloid leukemia (AML) , uterine cancer, gastro-esophageal cancer, and rectal adenocarcinoma.
  • lung cancer colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, cholangiocarcinoma, liver cancer, cervical cancer, endometrial cancer, ovarian cancer, peritoneal cancer, urothelial cancer, bladder cancer, gastric cancer, thyroid cancer, melanoma, breast cancer, head and neck cancer,
  • the agent that blocks the interaction between CD47 and SIRP ⁇ and the anti-HER2 ADC are administered simultaneously. In some embodiments, the agent that blocks the interaction between CD47 and SIRP ⁇ and the anti-HER2 ADC are administered sequentially. In some embodiments, the agent that blocks the interaction between CD47 and SIRP ⁇ is administered prior to the anti-HER2 ADC. In some embodiments, the anti-HER2 ADC is administered prior to the agent that blocks the interaction between CD47 and SIRP ⁇ .
  • FIG. 1A provides a schematic of the anti-HER2 antibody-drug conjugate trastuzumab emtansine
  • FIG. 1B provides a schematic of the anti-HER2 antibody-drug conjugate trastuzumab deruxtecan (DS8201) .
  • FIG. 1C provides a schematic of the anti-HER2 antibody-drug conjugate disitamab vedotin (RC48) .
  • FIG. 2A provides the results of experiments that were performed to compare the efficacy of (a) PBS (control) , (b) TJC4 monotherapy, (c) trastuzumab deruxtecan (DS8201) monotherapy and (d) TJC4 in combination with trastuzumab deruxtecan (DS8201) in inhibiting tumor in mice bearing human MDA-MB-231 breast cancer tumor xenografts.
  • TJC4 is an anti-CD47 antibody comprising a heavy chain that comprises SEQ ID NO: 3 or 35 and a light chain that comprises SEQ ID NO: 4.
  • FIG. 2B provides the results of experiments that were performed to compare the efficacy of (a) PBS (control) , (b) TJC4 monotherapy, (c) Disitamab vedotin (RC48) monotherapy and (d) TJC4 in combination with Disitamab vedotin (RC48) in inhibiting tumor growth in mice bearing human MDA-MB-231 breast cancer tumor xenografts.
  • FIG. 2C provides the results of experiments that were performed to compare the efficacy of (a) PBS (control) , (b) TJC4 monotherapy, (c) trastuzumab deruxtecan (DS8201) monotherapy and (d) TJC4 in combination with trastuzumab deruxtecan (DS8201) in inhibiting tumor growth in mice bearing human NCI-N87 gastric cancer tumor xenografts.
  • FIG. 2D provides the results of experiments that were performed to compare the efficacy of (a) PBS (control) , (b) TJC4 monotherapy, (c) trastuzumab deruxtecan (DS8201) monotherapy and (d) TJC4 in combination with trastuzumab deruxtecan (DS8201) in inhibiting tumor growth in mice bearing human MCF-7 breast cancer tumor xenografts.
  • FIG 2E provides the results of flow cytometry experiments that were performed to assess the effects of treatment with (a) PBS (control) , (b) TJC4 monotherapy, (c) trastuzumab deruxtecan (DS8201) monotherapy and (d) TJC4 in combination with trastuzumab deruxtecan (DS8201) on the infiltration of MDA-MB-231 breast cancer tumor cells by macrophages.
  • FIG 2F provides the results of flow cytometry experiments that were performed to assess the effects of treatment with (a) PBS (control) , (b) TJC4 monotherapy, (c) trastuzumab deruxtecan (DS8201) monotherapy and (d) TJC4 in combination with trastuzumab deruxtecan (DS8201) on the infiltration of MDA-MB-231 breast cancer tumor cells by NK cells.
  • FIG 2G provides the results of flow cytometry experiments that were performed to assess the effects of treatment with (a) PBS (control) , (b) TJC4 monotherapy, (c) trastuzumab deruxtecan (DS8201) monotherapy and (d) TJC4 in combination with trastuzumab deruxtecan (DS8201) on the infiltration of MDA-MB-231 breast cancer tumor cells by cytotoxic NK cells.
  • FIG 2H provides the results of immunohistochemistry analyses that were performed to assess the effects of treatment with (a) PBS (control) , (b) TJC4 monotherapy, (c) trastuzumab deruxtecan (DS8201) monotherapy and (d) TJC4 in combination with trastuzumab deruxtecan (DS8201) on CD47 expression (left panel) and CD68 expression (right panel) of MDA-MB-231 breast cancer tumor cells.
  • FIG. 3A provides the results of experiments that were performed to compare the efficacy of a) PBS (control) , (b) TJC4 monotherapy, (c) Disitamab vedotin (RC48) monotherapy and (d) TJC4 in combination with Disitamab vedotin (RC48) in inhibiting tumor growth in mice bearing BRC008 patient-derived breast cancer tumor xenografts.
  • FIG. 3B provides the results of experiments that were performed to compare the efficacy of a) PBS (control) , (b) TJC4 monotherapy, (c) Disitamab vedotin (RC48) monotherapy and (d) TJC4 in combination with Disitamab vedotin (RC48) in inhibiting tumor growth for greater than 25 days in mice bearing ST-02-0079 patient-derived gastric cancer tumor xenografts.
  • FIG. 3C provides the results of experiments that were performed to compare the efficacy of a) PBS (control) , (b) TJC4 monotherapy, (c) Disitamab vedotin (RC48) monotherapy and (d) TJC4 in combination with Disitamab vedotin (RC48) in inhibiting tumor growth for greater than 25 days in mice bearing BR-05-0419 patient-derived breast cancer tumor xenografts.
  • FIG 4A provides the results of experiments that were performed to assess the expression levels of HER2 on human breast cancer cell lines MCF-7, MDA-MB-231, and BT-474, and in the human gastric cancer cell line NCI-N87.
  • FIG 4B provides the results of experiments that were performed to assess the expression levels of CD47 on human breast cancer cell lines MCF-7, MDA-MB-231, and BT-474, and in the human gastric cancer cell line NCI-N87.
  • FIG 5A provides the results of experiments that were performed to assess the effects of single agent TJC4, single agent anti-HER2 ADC, and TJC4 in combination with a HER2-ADC on NK cytolysis of human BT474 breast cancer cells.
  • FIG 5B provides the results of experiments that were performed to assess the effects of single agent TJC4, single agent anti-HER2 ADC, and TJC4 in combination with a HER2-ADC on macrophage phagocytosis of human BT474 breast cancer cells.
  • aspects and embodiments of the present disclosure include “comprising, ” “consisting, ” and “consisting essentially of” aspects and embodiments.
  • CD47 (which is also known as Integrin Associated Protein (IAP) , Antigenic Surface Determinant Protein OA3, OA3, CD47 Antigen, Rh-Related Antigen, Integrin-Associated Signal Transducer, Antigen Identified By Monoclonal Antibody 1D8, CD47 glycoprotein) preferably refers to human CD47 and, in particular, to a protein comprising the amino acid sequence
  • CD47 also refers to any post translationally modified variants and conformation variants.
  • an “immunoconjugate, ” “antibody-drug conjugate, ” or “ADC” refers to an antibody conjugated to one or more heterologous molecule (s) , including, but not limited to, a cytotoxic agent.
  • exemplary antibody-drug conjugates include anti-HER2 antibody-drug conjugates.
  • antibody is used in the broadest sense and specifically covers intact antibodies (e.g., full length antibodies) , antibody fragments (including without limitation Fab, F (ab’) 2, scFv, scFv-Fc, single domain antibodies, single heavy chain antibodies, and single light chain antibodies) , monoclonal antibodies, and polyclonal antibodies, so long as they exhibit the desired biological activity (e.g., epitope binding) .
  • an isolated antibody may refer to an antibody that is substantially free of other cellular material. In one embodiment, an isolated antibody is substantially free of other proteins from the same species. In another embodiment, an isolated antibody is expressed by a cell from a different species and is substantially free of other proteins from the different species. In some embodiments, an “isolated” antibody is one which has been identified and separated and/or recovered from a component of its natural environment. Contaminant components of its natural environment are materials which would interfere with diagnostic or therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or nonproteinaceous solutes.
  • an antibody may be rendered substantially free of naturally associated components (or components associated with the cellular expression system used to produce the antibody) by isolation, using protein purification techniques well known in the art.
  • the antibody will be purified (1) to greater than 75%by weight of antibody as determined by the Lowry method, and most preferably more than 80%, 90%, 95%or 99%by weight, or (2) to homogeneity by SDS-PAGE under reducing or nonreducing conditions using Coomassie blue or, preferably, silver stain.
  • Isolated antibody includes the antibody in situ within recombinant cells since at least one component of the antibody's natural environment will not be present. Ordinarily, however, isolated antibody will be prepared by at least one purification step.
  • epitopic determinants means any antigenic determinant on an antigen to which the paratope of an antibody binds.
  • Epitopic determinants 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.
  • the term “native antibodies and immunoglobulins” are usually heterotetrameric glycoproteins of about 150,000 daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Each light chain is linked to a heavy chain by one covalent disulfide bond (also termed a “VH/VL pair” ) , while the number of disulfide linkages varies between the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has at one end a variable domain (VH) followed by a number of constant domains.
  • VH variable domain
  • Each light chain has a variable domain at one end (VL) and a constant domain at its other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain.
  • Particular amino acid residues are believed to form an interface between the light-and heavy-chain variable domains. See, e.g., Chothia et al., J. Mol. Biol., 186: 651 (1985) ; Novotny and Haber, Proc. Natl. Acad. Sci. U.S.A., 82: 4592 (1985) .
  • variable refers to the fact that certain portions of the variable domains differ extensively in sequence among antibodies and are used in the binding and specificity of each particular antibody for its particular antigen. However, the variability is not evenly distributed throughout the variable domains of antibodies. It is concentrated in three segments called complementarity-determining regions (CDRs) or hypervariable regions both in the light-chain and the heavy-chain variable domains. The more highly conserved portions of variable domains are called the framework (FR) .
  • CDRs complementarity-determining regions
  • FR framework
  • the variable domains of native heavy and light chains each comprise four FR regions, largely adopting a ⁇ -sheet configuration, connected by three CDRs, which form loops connecting, and in some cases forming part of, the ⁇ -sheet structure.
  • the CDRs in each chain are held together in close proximity by the FR regions and, with the CDRs from the other chain, contribute to the formation of the antigen-binding site of antibodies. See, e.g., Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, National Institute of Health, Bethesda, Md. (1991) .
  • the constant domains are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular toxicity.
  • Variable region sequences of interest include the humanized variable region sequences for CD47 antibodies described in detail elsewhere herein.
  • hypervariable region or “complementarity determining region (CDR) ” may refer to the subregions of the VH and VL domains characterized by enhanced sequence variability and/or formation of defined loops. These include three CDRs in the VH domain (H1, H2, and H3) and three CDRs in the VL domain (L1, L2, and L3) . H3 is believed to be critical in imparting fine binding specificity, with L3 and H3 showing the highest level of diversity. See Johnson and Wu, in Methods in Molecular Biology 248: 1-25 (Lo, ed., Human Press, Totowa, N.J., 2003) .
  • CDR/HVR delineations A number of CDR/HVR delineations are known.
  • the Kabat Complementarity Determining Regions are based on sequence variability and are the most commonly used (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991) ) . Chothia refers instead to the location of the structural loops (Chothia and Lesk J. Mol. Biol. 196: 901-917 (1987) ) .
  • the AbM HVRs represent a compromise between the Kabat HVRs and Chothia structural loops, and are used by Oxford Molecular's AbM antibody modeling software.
  • the “contact” HVRs are based on an analysis of the available complex crystal structures. The residues from each of these HVRs/CDRs are noted below. “Framework” or “FR” residues are those variable domain residues other than the HVR/CDR residues
  • Extended HVRs are also known: 24-36 or 24-34 (L1) , 46-56 or 50-56 (L2) and 89-97 or 89-96 (L3) in the VL and 26-35 (H1) , 50-65 or 49-65 (H2) and 93-102, 94-102, or 95-102 (H3) in the VH (Kabat numbering) .
  • “Numbering according to Kabat” may refer to the numbering system used for heavy chain variable domains or light chain variable domains of the compilation of antibodies in Kabat et al., supra.
  • the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of, or insertion into, a FR or HVR of the variable domain.
  • the Kabat numbering of residues may be determined for a given antibody by alignment at regions of homology of the sequence of the antibody with a “standard” Kabat numbered sequence.
  • the Kabat numbering is used when referring to a residue in the variable domains (approximately residues 1-107 of the light chain and residues 1-113 of the heavy chain)
  • the EU numbering system or index e.g., the EU index as in Kabat, numbering according to EU IgG1
  • EU index is generally used when referring to a residue in the heavy chain constant region.
  • epitope refers to the specific group of atoms or amino acids on an antigen to which an antibody or antibody moiety binds. Two antibodies or antibody moieties may bind the same epitope within an antigen if they exhibit competitive binding for the antigen.
  • a first antibody or fragment thereof “competes” for binding to a target antigen with a second antibody or fragment thereof when the first antibody or fragment thereof inhibits the target antigen binding of the second antibody of fragment thereof by at least about 50%(such as at least about any one of 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%or 99%) in the presence of an equimolar concentration of the first antibody or fragment thereof, or vice versa.
  • a high throughput process for “binning” antibodies based upon their cross-competition is described in PCT Publication No. WO 03/48731.
  • a “monoclonal” antibody refers to an antibody obtained from a population of substantially homogeneous antibodies, e.g., substantially identical but allowing for minor levels of background mutations and/or modifications. “Monoclonal” denotes the substantially homogeneous character of antibodies, and does not require production of the antibody by any particular method.
  • a monoclonal antibody is selected by its HVR, VH, and/or VL sequences and/or binding properties, e.g., selected from a pool of clones (e.g., recombinant, hybridoma, or phage-derived) .
  • a monoclonal antibody may be engineered to include one or more mutations, e.g., to affect binding affinity or other properties of the antibody, create a humanized or chimeric antibody, improve antibody production and/or homogeneity, engineer a multispecific antibody, resultant antibodies of which are still considered to be monoclonal in nature.
  • a population of monoclonal antibodies may be distinguished from polyclonal antibodies as the individual monoclonal antibodies of the population recognize the same antigenic site.
  • phage-display technologies see, e.g., Clackson et al., Nature, 352: 624-628 (1991) ; Marks et al., J. Mol. Biol. 222: 581-597 (1992) ; Sidhu et al., J. Mol. Biol. 338 (2) : 299-310 (2004) ; Lee et al., J. Mol. Biol. 340 (5) : 1073-1093 (2004) ; Fellouse, Proc. Natl. Acad. Sci. USA 101 (34) : 12467-12472 (2004) ; and Lee et al., J. Immunol.
  • Methods 284 (1-2) 119-132 (2004) , and technologies for producing human or human-like antibodies in animals that have parts or all of the human immunoglobulin loci or genes encoding human immunoglobulin sequences (see, e.g., WO 1998/24893; WO 1996/34096; WO 1996/33735; WO 1991/10741; Jakobovits et al., Proc. Natl. Acad. Sci. USA 90: 2551 (1993) ; Jakobovits et al., Nature 362: 255-258 (1993) ; Bruggemann et al., Year in Immunol. 7: 33 (1993) ; U.S. Pat. Nos.
  • Chimeric antibodies may refer to an antibody with one portion of the heavy and/or light chain from a particular isotype, class, or organism and another portion from another isotype, class, or organism.
  • the variable region will be from one source or organism, and the constant region will be from another.
  • Humanized antibodies may refer to antibodies with predominantly human sequence and a minimal amount of non-human (e.g., mouse or chicken) sequence.
  • a humanized antibody has one or more HVR sequences (bearing a binding specificity of interest) from an antibody derived from a non-human (e.g., mouse or chicken) organism grafted onto a human recipient antibody framework (FR) .
  • non-human residues are further grafted onto the human framework (not present in either source or recipient antibodies) , e.g., to improve antibody properties.
  • a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, 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 FRs are those of a human immunoglobulin sequence.
  • the humanized antibody optionally will also comprise at least a portion of an immunoglobulin constant region (Fc) , typically that of a human immunoglobulin. See Jones et al., Nature 321: 522-525 (1986) ; Riechmann et al., Nature 332: 323-329 (1988) ; and Presta, Curr. Op. Struct. Biol. 2: 593-596 (1992) .
  • a “human” antibody may refer to an antibody having an amino acid sequence which corresponds to that of an antibody produced by a human and/or has been made using any of the techniques for making human antibodies as disclosed herein.
  • Human antibodies can be produced using various techniques known in the art, including phage-display libraries. Hoogenboom and Winter, J. Mol. Biol., 227: 381 (1991) ; Marks et al., J. Mol. Biol., 222: 581 (1991) ; preparation of human monoclonal antibodies as described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985) ; Boerner et al., J.
  • immunized xenomice see, e.g., U.S. Pat. Nos. 6,075,181 and 6,150,584 regarding XENOMOUSE TM technology
  • chickens with human immunoglobulin sequence (s) see, e.g., WO2012162422, WO2011019844, and WO2013059159
  • immunoglobulins There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these can be further divided into subclasses (isotypes) , e.g., IgG1, IgG2, IgG3, IgG4, IgA1, IgA2.
  • the heavy-chain constant domains that correspond to the different classes of immunoglobulins are called ⁇ , ⁇ , ⁇ , ⁇ , and ⁇ , respectively.
  • the subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.
  • antibody fragment and all grammatical variants thereof, are defined as a portion of an intact antibody comprising the antigen binding site or variable region of the intact antibody which, in certain instances, is free of the constant heavy chain domains (i.e. CH2, CH3, and/or CH4, depending on antibody isotype) of the Fc region of the intact antibody.
  • antibody fragments include Fab, Fab’, Fab’-SH, F (ab’) 2 , and Fv fragments; diabodies; any antibody fragment that is a polypeptide having a primary structure consisting of one uninterrupted sequence of contiguous amino acid residues (referred to herein as a “single-chain antibody fragment” or “single chain polypeptide” ) , including without limitation (1) single-chain Fv (scFv) molecules, (2) single chain polypeptides containing only one light chain variable domain, or a fragment thereof that contains the three CDRs of the light chain variable domain, without an associated heavy chain moiety, and (3) single chain polypeptides containing only one heavy chain variable region, or a fragment thereof containing the three CDRs of the heavy chain variable region, without an associated light chain moiety; and multi-specific or multivalent structures formed from antibody fragments.
  • the heavy chain (s) can contain any constant domain sequence (e.g. CH1 in the IgG isotype) found in a non-Fc region of an intact antibody, and/or can contain any hinge region sequence found in an intact antibody, and/or can contain a leucine zipper sequence fused to or situated in the hinge region sequence or the constant domain sequence of the heavy chain (s) .
  • any constant domain sequence e.g. CH1 in the IgG isotype
  • Papain digestion of antibodies produces two identical antigen-binding fragments, called “Fab” fragments, each with a single antigen-binding site, and a residual “Fc” fragment, whose name reflects its ability to crystallize readily.
  • Pepsin treatment yields an F (ab’ ) 2 fragment that has two antigen-combining sites and is still capable of cross-linking antigen.
  • Fv is the minimum antibody fragment which contains a complete antigen-recognition and -binding site. In a two-chain Fv species, this region consists of a dimer of one heavy-and one light-chain variable domain in tight, non-covalent association.
  • one heavy-and one light-chain variable domain can be covalently linked by a flexible peptide linker such that the light and heavy chains can associate in a “dimeric” structure analogous to that in a two-chain Fv species. It is in this configuration that the three CDRs of each variable domain interact to define an antigen-binding site on the surface of the VH-VL dimer. Collectively, the six CDRs confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.
  • the Fab fragment also contains the constant domain of the light chain and the first constant domain (CH 1 ) of the heavy chain.
  • Fab’ fragments differ from Fab fragments by the addition of a few residues at the carboxy terminus of the heavy chain CH 1 domain including one or more cysteines from the antibody hinge region.
  • Fab’-SH is the designation herein for Fab’ in which the cysteine residue (s) of the constant domains bear a free thiol group.
  • F (ab’) 2 antibody fragments originally were produced as pairs of Fab’ fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.
  • the term “monoclonal antibody” refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Each mAb is directed against a single determinant on the antigen. In addition to their specificity, the monoclonal antibodies are advantageous in that they can be synthesized by hybridoma culture, uncontaminated by other immunoglobulins.
  • the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
  • the monoclonal antibodies to be used in accordance with the present invention may be made in an immortalized B cell or hybridoma thereof, or may be made by recombinant DNA methods.
  • the monoclonal antibodies herein include hybrid and recombinant antibodies produced by splicing a variable (including hypervariable) domain of an CD47 antibody with a constant domain (e.g. “humanized” antibodies) , or a light chain with a heavy chain, or a chain from one species with a chain from another species, or fusions with heterologous proteins, regardless of species of origin or immunoglobulin class or subclass designation, as well as antibody fragments (e.g., Fab, F (ab’) 2 , and Fv) , so long as they exhibit the desired biological activity.
  • Fab fragment antigen binding
  • the monoclonal antibodies herein specifically include chimeric antibodies (immunoglobulins) in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species 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 antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity.
  • chimeric antibodies immunoglobulins in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species 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 antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity.
  • treatment refers to clinical intervention designed to alter the natural course of the individual or cell being treated during the course of clinical pathology. Desirable effects of treatment include decreasing the rate of disease progression, ameliorating, or palliating the disease state, and remission or improved prognosis.
  • an individual is successfully “treated” if one or more symptoms associated with cancer are mitigated or eliminated, including, but are not limited to, reducing the proliferation of (or destroying) cancerous cells, decreasing symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, and/or prolonging survival of individuals.
  • “treating” a disease such as cancer refers to delaying progression of the disease, i.e., deferring, hindering, slowing, retarding, stabilizing, and/or postponing development of the disease (such as cancer) .
  • This delay can be of varying lengths of time, depending on the history of the disease and/or individual being treated.
  • a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease.
  • a late stage cancer such as development of metastasis, may be delayed.
  • an “effective amount” is at least the minimum amount required to effect a measurable improvement or prevention of a particular disease (e.g., cancer) .
  • An effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of a therapeutic agent (or combination of therapeutic agents) to elicit a desired response in the individual.
  • An effective amount is also one in which any toxic or detrimental effects of the treatment are outweighed by the therapeutically beneficial effects.
  • beneficial or desired results include clinical results such as decreasing one or more symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease, and/or prolonging survival.
  • an effective amount of the drug may have the effect in reducing the number of cancer cells; reducing the tumor size; inhibiting (i.e., slow to some extent or desirably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and desirably stop) tumor metastasis; inhibiting to some extent tumor growth; and/or relieving to some extent one or more of the symptoms associated with the disorder.
  • An effective amount can be administered in one or more administrations.
  • an effective amount of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish therapeutic treatment either directly or indirectly.
  • an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition.
  • an “effective amount” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.
  • the term “subject” for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, etc.
  • the mammal is human.
  • the present application is based on the unexpected finding that a combination treatment comprising an anti-HER2 antibody-drug conjugate (e.g., trastuzumab deruxtecan) and an agent that blocks the interaction between CD47 and SIRP ⁇ (e.g., an anti-CD47 antibody can synergistically inhibit tumor growth than either drug alone, regardless of the tumor’s HER2 expression level, for example, in HER2 low expression tumors.
  • an anti-HER2 antibody-drug conjugate e.g., trastuzumab deruxtecan
  • an agent that blocks the interaction between CD47 and SIRP ⁇ e.g., an anti-CD47 antibody can synergistically inhibit tumor growth than either drug alone, regardless of the tumor’s HER2 expression level, for example, in HER2 low expression tumors.
  • a method of treating tumor (s) in a subject comprising administering to the subject an effective amount of an agent (e.g., a therapeutic agent) that blocks the interaction between CD47 (e.g., hCD47) and SIRP ⁇ (e.g., hSIRP ⁇ ) and an effective amount of an anti-HER2 antibody-drug conjugate (ADC) .
  • an agent e.g., a therapeutic agent
  • CD47 e.g., hCD47
  • SIRP ⁇ e.g., hSIRP ⁇
  • ADC anti-HER2 antibody-drug conjugate
  • HER2 (which is also known as ERBB2, NEU, CD340, HER-2/neu, MLN 19, NGL, TKR1, and erb-b2 receptor tyrosine kinase 2) refers to human HER2 and, in particular, to a protein having the amino acid sequence SEQ ID NO: 37 or a variant of said amino acid sequence.
  • the subject is a human subject.
  • the subject s tumor (s) express HER2.
  • HER2 refers to any post translationally modified variant and conformation variant of SEQ ID NO: 37.
  • the tumor (s) express HER2 at a level of HER2 1+, HER2 2+ or HER2 3+ as determined by immunohistochemistry (IHC) .
  • the immunohistochemistry (IHC) test is commonly used to measure the amount of HER2 receptor protein expressed on the surface and/or in the cytoplasm of cells in a tissue sample (such as a cancerous tissue sample or a tumor sample) from the subject, e.g., a breast cancer tissue sample or a gastric cancer tissue sample.
  • IHC testing is performed on sample comprising cells from the subject’s tumor (s) .
  • the sample (e.g., the cancerous tissue sample or tumor sample) comprises or is derived from a fresh tissue sample or a fresh tumor sample (e.g., a tissue or tumor sample that has not been frozen) .
  • the sample (e.g., the cancerous tissue sample or tumor sample) comprises or is derived from a frozen tissue sample or frozen tumor sample (e.g., a tissue or tumor sample that was frozen after being biopsied) .
  • the sample (e.g., the cancerous tissue sample or tumor sample) is a fixed sample, e.g., a formalin-fixed paraffin-embedded (FFPE) sample.
  • FFPE formalin-fixed paraffin-embedded
  • the sample (e.g., the cancerous tissue sample or tumor sample) is assigned a score of 0, 1+, 2+, or 3+. See, e.g., Hicks et al. 2011) Laboratory Medicine, 42 (8) : 459–467.
  • a tissue sample that has been determined via IHC to have a HER2 score of 0 or 1+ is “HER2 negative” (e.g., a HER2-negative tumor) .
  • a tissue sample that has been determined via IHC to have a HER2 score of 2+ is “borderline” or “equivocal” (e.g., a borderline tumor or an equivocal tumor) .
  • a tissue sample that has been determined via IHC to have a HER2 score of 3+ is “HER2 positive” (e.g., a HER2 positive tumor) .
  • the tissue sample (e.g., tumor sample) from the subject has been determined via IHC to have a HER2 score of 2+ or lower (e.g., 2+, 1+, or 0) .
  • Fluorescent in situ hybridization is a method that is commonly used to detect HER2 gene amplification in a sample (e.g., a cancerous tissue sample or tumor sample) from a subject. See, e.g., Press et al. (2016) J Clin Oncol, 34 (29) : 3518-3528 and references cited therein.
  • FISH is performed on sample comprising cells from the subject’s tumor (s) or cells from cancerous tissue from the subject.
  • the sample e.g., the cancerous tissue sample or tumor sample
  • the sample (e.g., the cancerous tissue sample or tumor sample) comprises or is derived from a frozen tissue sample or frozen tumor sample (e.g., a tissue or tumor sample that was frozen after being biopsied) .
  • the sample e.g., the cancerous tissue sample or tumor sample
  • the sample is a fixed sample, e.g., a formalin-fixed paraffin-embedded (FFPE) sample.
  • FFPE formalin-fixed paraffin-embedded
  • the sample (e.g., the cancerous tissue sample or tumor sample from the subject) ) has been determined via FISH to be “FISH+”
  • FISH+ means that the FISH ratio (e.g., the HER2/CEP7 ratio) is greater than 2.2.
  • FISH+ means that the HER2 gene copy is greater than 6.0.
  • the sample e.g., the cancerous tissue sample or tumor sample from the subject
  • FISH equivocal means that the FISH ratio (e.g., the HER2/CEP7 ratio) is between 1.8 and 2.2.
  • FISH equivocal means that the HER2 gene copy is between 4.0 and 6.0.
  • the sample e.g., the cancerous tissue sample or tumor sample from the subject
  • FISH-means that the FISH ratio e.g., the HER2/CEP7 ratio
  • FISH-means that the HER2 gene copy is less than 4.0.
  • the sample e.g., the cancerous tissue sample or tumor sample from the subject
  • the sample has been determined (e.g., via IHC) to have a HER2 score of 3+ or 2+ and (e.g., via FISH) to be FISH+.
  • the sample e.g., the cancerous tissue sample or tumor sample from the subject
  • the tumor is a CD47 + tumor, e.g., a tumor that expresses CD47.
  • the tumor (s) express CD47 at a level of CD47 1+, CD47 2+ or CD47 3+ as determined by IHC.
  • IHC is also commonly used to measure the amount of CD47 receptor protein expressed on the surface and/or in the cytoplasm of cells in a tissue sample (such as a cancerous tissue sample or a tumor sample) from the subject, e.g., a breast cancer tissue sample or a gastric cancer tissue sample.
  • the IHC assay is performed using a commercially available anti-CD47 antibody.
  • IHC testing is performed on sample comprising cells from the subject’s tumor (s) .
  • the sample e.g., the cancerous tissue sample or tumor sample
  • the sample comprises or is derived from a fresh tissue sample or a fresh tumor sample (e.g., a tissue or tumor sample that has not been frozen) .
  • the sample e.g., the cancerous tissue sample or tumor sample
  • the sample e.g., the cancerous tissue sample or tumor sample
  • the sample is a fixed sample, e.g., a formalin-fixed paraffin-embedded (FFPE) sample.
  • FFPE formalin-fixed paraffin-embedded
  • the sample is assigned a score of 0, 1+, 2+, or 3+.
  • a CD47 IHC score of 0 means that no staining of the plasma membranes and no cytoplasmic staining was detected in the sample.
  • a CD47 IHC score of 0 means that the sample is “CD47 negative by IHC.
  • a CD47 IHC score of 1+ means that weak staining of the plasma membranes and cytoplasm was detected in the sample, e.g., via microscopy using a 20x objective lens. In some embodiments, a CD47 IHC score of 1+ means that the sample is “CD47 weak positive by IHC. ” In some embodiments, a CD47 IHC score of 2+ means that moderate staining of the plasma membranes and cytoplasm was detected in the sample, e.g., via microscopy using a 10x objective lens. In some embodiments, a CD47 IHC score of 2+ means that the sample is “CD47 moderate positive by IHC.
  • a CD47 IHC score of 3+ means that strong staining of the plasma membranes and cytoplasm was detected in the sample, e.g., via microscopy using a 4x objective lens. In some embodiments, a CD47 IHC score of 3+ means that the sample is “CD47 strong positive by IHC. ”
  • the cancer or tumor is selected from the group consisting of lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, cholangiocarcinoma, liver cancer, cervical cancer, endometrial cancer, ovarian cancer, peritoneal cancer, urothelial cancer, bladder cancer, gastric cancer, thyroid cancer, melanoma, breast cancer, head and neck cancer, multiple myeloma, acute myeloid leukemia (AML) , uterine cancer, gastro-esophageal cancer, rectal adenocarcinoma, and a tumor of any of the preceding.
  • lung cancer colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, cholangiocarcinoma, liver cancer, cervical cancer, endometrial cancer, ovarian cancer, peritoneal cancer, urothelial cancer, bladder cancer, gastric cancer, thyroid cancer, melanoma, breast cancer, head
  • AML acute myeloid leukemia
  • the agent e.g., a therapeutic agent
  • CD47 e.g., hCD47
  • SIRP ⁇ e.g., hSIRP ⁇
  • the agent is an anti-CD47 antibody or an immunologically active fragment thereof.
  • an anti-CD47 antibody (or an immunologically active fragment thereof) is an antibody or fragment that binds to CD47 (e.g., human CD47 or “hCD47” ) with sufficient affinity and specificity.
  • an “immunologically active fragment” of an antibody refers to an antigen-binding fragment of said antibody.
  • the terms “immunologically active fragment” and “antigen-binding fragment” are used interchangeably herein.
  • the anti-CD47 antibody (or immunologically active fragment thereof) is or comprises any antibody (or immunologically active fragment thereof) that binds to CD47 (e.g., human CD47) .
  • the anti-CD47 antibody (or immunologically active fragment thereof) is a chimeric (such as humanized) monoclonal antibody (or immunologically active fragment thereof) .
  • the anti-CD47 antibody is 5F9 (also known as Hu5F9-G4 and magrolimab) , which is under development by Gilead Sciences/Forty Seven, Inc.; CC-90002 (also known as INBRX103) , which is under development by Celgene; LQ001, which is under development by Novamab; HLX24, which is under development by Henlius; TI-061, which is under development by Arch Oncology (formerly Tioma Therapeutics) ; AO-176, which is under development by Arch Oncology; SRF-231, which is under development by Surface Oncology; IBI-188, which is under development by Innovent Bio; AK117, which is under development by Akesobio; IMC-002, which is under development by ImmuneOncia Therapeutics 3D Medicines; SHR-1603, which is under development by Jiangsu HengRui Medicine; STI-6643, which is under development by Sorrento Therapeutics Inc.; or ZL
  • the immunologically active fragment of the anti-CD47 antibody is an immunologically active fragment of any one of the preceding anti-CD47 antibodies. Additional details about these exemplary anti-CD47 antibodies can be found in, e.g., Jiang et al. (2021) J Hematol Oncol 14: 180 doi (dot) org/10 (dot) 1186/s13045-021-01197-w; WO 2011/143624A2, USP 9,382,320 B2.
  • the anti-CD47 antibody (or immunologically active fragment thereof) competes for binding to CD47 (e.g., human CD47) with an antibody moiety comprising a) a heavy variable region (V H ) and a light chain variable region (V L ) , wherein: a) the V H comprises: i) a HC-CDR1 comprising an amino acid sequence of SEQ ID NO: 5, ii) a HC-CDR2 comprising an amino acid sequence of SEQ ID NO: 6, and iii) a HC-CDR3 comprising an amino acid sequence of SEQ ID NO: 7, and; b) the V L comprises: (1) a CDR-L1 comprising KSSQSVLYAGNNRNYLA (SEQ ID NO: 8) ; (2) a CDR-L2 comprising QASTRAS (SEQ ID NO: 9) ; and (3) a CDR-L3 comprising QQYYTPPLA (SEQ ID NO: 10) .
  • CD47 e.g.
  • the anti-CD47 antibody (or immunologically active fragment thereof) comprises a heavy chain variable domain (V H ) , and/or a light chain variable domain (V L ) of described herein below.
  • the anti-CD47 antibody (or immunologically active fragment thereof) comprises a V H that comprises three complementarity determining regions (CDRs) of a heavy chain variable domain (V H ) set forth in SEQ ID NO: 1 and three CDRs of a light chain variable domain (V L ) set forth in SEQ ID NO: 2
  • the anti-CD47 antibody (or immunologically active fragment thereof) comprises a (a) VH domain that comprises (1) a CDR-H1 comprising RAWMN (SEQ ID NO: 5) ; (2) a CDR-H2 comprising RIKRKTDGETTDYAAPVKG (SEQ ID NO: 6) ; (3) a CDR-H3 comprising SNRAFDI (SEQ ID NO: 7) and (b) a VL domain that comprises (1) a CDR-L1 comprising KSSQSVLYAGNNRNYLA (SEQ ID NO: 8) ; (2) a CDR-L2 comprising QASTRAS (SEQ ID NO: 9) ; and (3) a CDR-L3 comprising QQYYTPPLA (SEQ ID NO: 10) .
  • VH domain that comprises (1) a CDR-H1 comprising RAWMN (SEQ ID NO: 5) ; (2) a CDR-H2 comprising RIKRKTDGETTDYAAPVKG (SEQ
  • the CDR sequences are defined according to Kabat (see, e.g., (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991) ) .
  • the anti-CD47 antibody (or immunologically active fragment thereof) comprises a (a) VH domain that comprises (1) a CDR-H1 comprising GLTFERA (SEQ ID NO: 11) ; (2) a CDR-H2 comprising KRKTDGET (SEQ ID NO: 12) ; (3) a CDR-H3 comprising SNRAFDI (SEQ ID NO: 13) and (b) a VL domain that comprises (1) a CDR-L1 comprising KSSQSVLYAGNNRNYLA (SEQ ID NO: 14) ; (2) a CDR-L2 comprising QASTRAS (SEQ ID NO: 15) ; and (3) a CDR-L3 comprising QQYYTPPLA (SEQ ID NO: 16) .
  • the CDR sequences are defined according to the Chothia numbering system (see, e.g., Chothia and Lesk (1986) EMBO J. 5 (4) : 823-6 and Al-Lazikani et al., (1997) JMB 273: 927-948) .
  • the anti-CD47 antibody (or immunologically active fragment thereof) comprises a (a) VH domain that comprises (1) a CDR-H1 comprising GLTFERAW (SEQ ID NO: 17) ; (2) a CDR-H2 comprising IKRKTDGETT (SEQ ID NO: 18) ; (3) a CDR-H3 comprising AGSNRAFDI (SEQ ID NO: 19) and (b) a VL domain that comprises (1) a CDR-L1 comprising QSVLYAGNNRNY (SEQ ID NO: 20) ; (2) a CDR-L2 comprising QAS (SEQ ID NO: 21) ; and (3) a CDR-L3 comprising QQYYTPPLA (SEQ ID NO: 22) .
  • the CDR sequences are defined according to the IMGT numbering system (see, e.g., Lefranc MP. (2013) IMGT Unique Numbering. In: Dubitzky W., Wolkenhauer O., Cho KH., Yokota H. (eds) Encyclopedia of Systems Biology. Springer, New York, NY; https: //doi. org/10.1007/978-1-4419-9863-7_127) .
  • the anti-CD47 antibody (or immunologically active fragment thereof) comprises a (a) VH domain that comprises (1) a CDR-H1 comprising GLTFERAWMN (SEQ ID NO: 23) ; (2) a CDR-H2 comprising RIKRKTDGETTD (SEQ ID NO: 24) ; (3) a CDR-H3 comprising SNRAFDI (SEQ ID NO: 25) and (b) a VL domain that comprises (1) a CDR-L1 comprising KSSQSVLYAGNNRNYLA (SEQ ID NO: 26) ; (2) a CDR-L2 comprising QASTRAS (SEQ ID NO: 27) ; and (3) a CDR-L3 comprising QQYYTPPLA (SEQ ID NO: 28) .
  • VH domain that comprises (1) a CDR-H1 comprising GLTFERAWMN (SEQ ID NO: 23) ; (2) a CDR-H2 comprising RIKRKTDGETTD (SEQ ID NO: 24
  • the CDR sequences are defined according to the AbM numbering system (see, e.g., Abhinandan R. K., Martin A. C. Analysis and improvements to Kabat and structurally correct numbering of antibody variable domains. Mol. Immunol. 2008; 45: 3832–3839. doi: 10.1016/j. molimm. 2008.05.022) .
  • the anti-CD47 antibody (or immunologically active fragment thereof) comprises (a) VH domain that comprises (1) a CDR-H1 comprising ERAWMN (SEQ ID NO: 29) ; (2) a CDR-H2 comprising WVGRIKRKTDGETTD (SEQ ID NO: 30) ; (3) a CDR-H3 comprising AGSNRAFD (SEQ ID NO: 31) and (b) a VL domain that comprises (1) a CDR-L1 comprising LYAGNNRNYLAWY (SEQ ID NO: 32) ; (2) a CDR-L2 comprising LLINQASTRA (SEQ ID NO: 33) ; and (3) a CDR-L3 comprising QQYYTPPL (SEQ ID NO: 34) .
  • the CDR sequences are defined according to the Contact numbering system (see, e.g., McCallum et al. (1996) J Mol Biol. 262 (5) : 732-45; doi: 10.1006/jmbi. 1996.0548) .
  • the anti-CD47 antibody (or immunologically active fragment thereof) comprises 3 CDRs of a VH domain comprising SEQ ID NO: 1. Additionally or alternatively, in some embodiments, the anti-CD47 antibody (or immunologically active fragment thereof) comprises 3 CDRs of a VL domain comprising SEQ ID NO: 2. In some embodiments, the 3 CDRs of the VH domain are CDRs according to Kabat, Chothia, AbM or Contact numbering system. Additionally or alternatively, in some embodiments, the 3 CDRs of the VL domain are CDRs according to Kabat, Chothia, AbM or Contact numbering system.
  • the N-terminal amino acid of the VH domain of the anti-CD47 antibody (or immunologically active fragment thereof) is E, and, optionally, in some embodiments, the C-terminal amino acid of the VH domain of the anti-CD47 antibody (or immunologically active fragment thereof) is S.
  • the anti-CD47 antibody (or immunologically active fragment thereof) comprises a heavy chain variable domain (VH) comprising an amino acid sequence that has at least about 95%, 96%, 97%, 98%, 99%, or 100%sequence identity to an amino acid sequence set forth in SEQ ID NO: 1.
  • VH heavy chain variable domain
  • the N-terminal amino acid of the VH domain that has at least about 95%, 96%, 97%, 98%, 99%, or 100%sequence identity to an amino acid sequence set forth in SEQ ID NO: 1 is E.
  • the C-terminal amino acid of the VH domain that has at least about 95%, 96%, 97%, 98%, 99%, or 100%sequence identity to an amino acid sequence set forth in SEQ ID NO: 1 is S.
  • the N-terminal amino acid of the V H domain of the anti-CD47 antibody (or immunologically active fragment thereof) corresponds to position H1 according to the Kabat numbering system
  • the C-terminal amino acid of the V H domain of the anti-CD47 antibody (or immunologically active fragment thereof) corresponds to position H113 according to the Kabat numbering system.
  • the N-terminal amino acid of the V H domain of the anti-CD47 antibody corresponds to position H1 according to the Chothia numbering system
  • the C-terminal amino acid of the V H domain of the anti-CD47 antibody corresponds to position H113 according to the Chothia numbering system
  • the N-terminal amino acid of the V H domain of the anti-CD47 antibody corresponds to position H1 according to the IMGT numbering system
  • the C-terminal amino acid of the V H domain of the anti-CD47 antibody (or immunologically active fragment thereof) corresponds to position H128 according to the IMGT numbering system.
  • the N-terminal amino acid of the V H domain of the anti-CD47 antibody corresponds to amino acid 1 of SEQ ID NO: 1
  • the C-terminal amino acid of the V H domain the anti-CD47 antibody corresponds to amino acid 118 of SEQ ID NO: 1.
  • the anti-CD47 antibody comprises (such as further comprises) a light chain variable domain (VL) comprising an amino acid sequence that has at least about 95%, 96%, 97%, 98%, 99%, or 100%sequence identity to an amino acid sequence set forth in SEQ ID NO: 2.
  • VL light chain variable domain
  • the anti-CD47 antibody comprises a VH comprising SEQ ID NO: 1 and a VL comprising SEQ ID NO: 2. The amino acid sequences of SEQ ID NOs: 1 and 2 are provided below:
  • the anti-CD47 antibody is a full length antibody.
  • the full length antibody comprises a human Fc region.
  • the human Fc region is an IgG1, IgG2, or IgG4 Fc region.
  • the full length anti-CD47 antibody comprises a human IgG4 Fc region or a variant thereof that comprises an S228P substitution, wherein amino acid numbering is according to the EU index.
  • the full length anti-CD47 antibody comprises a heavy chain comprising the amino acid SEQ ID NO: 3 and a light chain comprising the amino acid sequence of SEQ ID NO: 4.
  • the full length anti-CD47 antibody is a full length antibody that comprises a heavy chain comprising the amino acid SEQ ID NO: 35 and a light chain comprising the amino acid sequence of SEQ ID NO: 4.
  • the anti-CD47 antibody is lemzoparlimab.
  • the anti-CD47 antibody that binds specifically to hCD47 can be of any of the various types of antibodies as defined above, but is, in certain embodiments, a human, humanized, or chimeric antibody. In some embodiments, the anti-CD47 antibody is a human antibody.
  • the anti-CD47 is a humanized antibody that comprises a human antibody constant domain (e.g., a human Fc domain, such as a human IgG Fc domain, e.g., a human IgG1, a human IgG2, a human IgG3, or a human IgG4 Fc domain, or a variant of a human IgG4 Fc domain that comprises an S228P substitution, wherein amino acid numbering is according to the EU index. ) .
  • the anti-CD47 antibody is a chimeric antibody. See, e.g., U.S. Patent No. 4,816,567 and Morrison et al., Proc. Natl. Acad. Sci.
  • the chimeric anti-CD47 antibody comprises a non-human variable region (e.g., a variable region derived from a chicken, mouse, rat, hamster, rabbit, or non-human primate, such as a monkey) and a human constant region.
  • a chimeric antibody is a “class switched” antibody in which the class or subclass has been changed from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof.
  • a chimeric antibody is a humanized antibody.
  • a non-human antibody can be humanized to reduce immunogenicity to humans, while retaining the specificity and affinity of the parental non-human antibody.
  • a humanized antibody comprises one or more variable domains in which HVRs, e.g., CDRs, (or portions thereof) are derived from a non-human antibody (e.g., a chicken antibody) , and FRs (or portions thereof) are derived from human antibody sequences.
  • HVRs e.g., CDRs
  • FRs or portions thereof
  • a humanized antibody optionally will also comprise at least a portion of a human constant region.
  • some FR residues in a humanized antibody are substituted with corresponding residues from a non-human antibody (e.g., the antibody from which the HVR or CDR residues are derived) , e.g., to restore or improve antibody specificity or affinity.
  • a non-human antibody e.g., the antibody from which the HVR or CDR residues are derived
  • Humanized antibodies and methods of making them are reviewed, e.g., in Almagro and Fransson, Front. Biosci. 13: 1619-1633 (2008) .
  • Human framework regions useful for humanization include but are not limited to: framework regions selected using the “best-fit” method; framework regions derived from the consensus sequence of human antibodies of a particular subgroup of light or heavy chain variable regions; human somatically mutated framework regions or human germline framework regions; and framework regions derived from screening FR libraries. See, e.g., Sims et al. J. Immunol. 151: 2296 (1993) ; Carter et al. Proc. Natl. Acad. Sci. USA, 89: 4285 (1992) ; Presta et al. J. Immunol., 151: 2623 (1993) ; Almagro and Fransson, Front. Biosci. 13: 1619-1633 (2008) ; and Baca et al., J. Biol. Chem. 272: 10678-10684 (1997) .
  • an anti-CD47 antibody of the present disclosure is a human antibody.
  • Human antibodies can be produced using various techniques known in the art.
  • the human antibody is produced by a non-human animal, such as the genetically engineered chickens (see, e.g., US Pat. Nos. 8,592,644; and 9,380,769) and/or mice described herein. Human antibodies are described generally in Lonberg, Curr. Opin. Immunol. 20: 450-459 (2008) .
  • an anti-CD47 antibody of the present disclosure is an antibody fragment (e.g., an immunologically active fragment) , including without limitation a Fab, F (ab’) 2, Fab’-SH, Fv, or scFv fragment, or a single domain, single heavy chain, or single light chain antibody.
  • an “immunologically active fragment” of an antibody refers to an antigen-binding fragment of said antibody.
  • the terms “immunologically active fragment” and “antigen-binding fragment” are used interchangeably herein.
  • Antibody fragments can be generated, e.g., by enzymatic digestion or by recombinant techniques.
  • an antibody fragment is produced by a recombinant host cell.
  • Fab, Fv and ScFv antibody fragments are expressed by and secreted from E. coli.
  • Antibody fragments can alternatively be isolated from an antibody phage library. Other methods of generating immunologically active fragments of an antibody are well-known in the art.
  • the anti-CD47 antibody (or immunologically active fragment thereof) specifically recognizes (such as binds) to hCD47 expressed on the surface of a cell.
  • the anti-CD47 antibody specifically recognizes hCD47 expressed on the surface of a cancer cell, e.g., cancer cell that has been determined via IHC to have a HER2 score of 1+, 2+ or 3+.
  • Exemplary cancers include, but are not limited to, lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, cholangiocarcinoma, liver cancer, cervical cancer, endometrial cancer, ovarian cancer, peritoneal cancer, urothelial cancer, bladder cancer, gastric cancer, thyroid cancer, melanoma, breast cancer, head and neck cancer, multiple myeloma, acute myeloid leukemia (AML) , uterine cancer, gastro-esophageal cancer, and rectal adenocarcinoma.
  • lung cancer colon adenocarcinoma
  • colorectal adenocarcinoma pancreatic cancer
  • cholangiocarcinoma cholangiocarcinoma
  • liver cancer cervical cancer
  • endometrial cancer ovarian cancer
  • peritoneal cancer urothelial cancer
  • bladder cancer gastric cancer
  • thyroid cancer melanoma
  • breast cancer head and
  • the binding of an anti-CD47 antibody (or immunologically active fragment thereof) described herein to hCD47 prevents the interaction of hCD47 with signal regulatory protein alpha (SIRP ⁇ ) , such as human SIRP ⁇ ( “hSIRP ⁇ ” ) .
  • SIRP ⁇ signal regulatory protein alpha
  • the term “anti-HER2 immunoconjugate” or “anti-HER2 antibody-drug conjugate (ADC) ” refers to any therapeutic agent comprising an anti-HER2 antibody (or an antigen-binding fragment thereof) conjugated (e.g., via molecular linker) to a drug or “payload. ”
  • the drug is a cytotoxic agent.
  • cytotoxic agent refers to a substance that reduces or blocks the function, or growth, of cells and/or causes destruction of cells. Any cytotoxic agent would be suitable so long as its conjugation to the anti-HER2 antibody does not substantially reduce a desired function and/or characteristic of the anti-HER2 antibody.
  • the drug or “payload” is covalently attached, directly or via a cleavable or noncleavable linker, to the anti-HER2 antibody.
  • the anti-HER2 ADC comprises any antibody (or antigen-binding fragment thereof) that binds HER2 (e.g., human HER2) .
  • the anti-HER2 antibody (or antigen binding fragment thereof) comprises trastuzumab (CAS Number 180288-69-1, also known as trastuzumab-anns, trastuzumab-dkst, trastuzumab-dttb, trastuzumab-pkrb, and trastuzumab-qyyp) , pertuzumab (CAS Number 380610-27-5, also known as and 2C4) .
  • the drug or payload of the anti-HER2 ADC comprises a cytotoxic agent.
  • cytotoxic agent refers to a substance that reduces or blocks the function, or growth, of cells and/or causes destruction of cells.
  • the cytotoxic agent is or comprises, without limitation, e.g., a radioactive isotope, a chemotherapeutic agent, or a toxin.
  • said toxin is or comprises, without limitation, e.g., an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof, a chemotherapeutic agent, a cell growth inhibitor, calichemicin, maytansine or maytansinoid, a small molecule drug, a prodrug, a taxoid, a tomaymycin derivative, a leptomycin derivative, CC-1065 or a CC-1065 analog, calichemicin, or trichothene.
  • an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof e.g., an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof, a chemotherapeutic agent, a cell growth inhibitor, calichemicin, maytansine or maytansinoid, a small molecule drug, a prodrug, a taxoid, a
  • the anti-HER2 ADC is trastuzumab emtansine (also known as ado-trastuzumab emtansine, trastuzumab-DM1, T-DM1 and ) , which is under development by Genentech/Roche; trastuzumab deruxtecan (also known as T-DXd, DS8201, DS8201a, and ) , which is under development by Daiichi-Sankyo and AstraZeneca; RC48 (also known as RC48-ADC, and disitamab vedotin) , which is under development by Remegen Biosciences and Yantai Rongchang Biological Engineering; SYD985, which is under development by Bydonis B.
  • trastuzumab emtansine also known as ado-trastuzumab emtansine, trastuzumab-DM1, T-DM1 and
  • FS-1502 which is under development by Shanghai Fosun Pharmaceutical Development Co, Ltd.
  • ALT-P7 which is under development by Alteogen, Inc.
  • DHES0815A which is under Genentech
  • MEDI4276 which is under MedImmune. Additional details regarding these anti-HER2 ADC are provided elsewhere herein.
  • the anti-HER2 ADC is trastuzumab emtansine (also known as ado-trastuzumab emtansine, trastuzumab-DM1, T-DM1 and ) , which is under development by Genentech/Roche.
  • Trastuzumab emtansine consists of the humanized monoclonal IgG1 antibody trastuzumab covalently linked to the cytotoxic agent DM1 (i.e., a microtubule-inhibitory maytansinoid) through a non-cleavable maleimidomethyl cyclohexane-1-carboxylate (MCC) linker (LoRusso et al.
  • MCC non-cleavable maleimidomethyl cyclohexane-1-carboxylate
  • trastuzumab emtansine undergoes receptor-mediated internalization into cells, is catabolized in lysosomes where DM1-containing catabolites are released and subsequently bind tubulin to cause mitotic arrest and cell death.
  • FIG. 1A A schematic of trastuzumab emtansine is provided in FIG. 1A.
  • the CAS Registry Number for trastuzumab emtansine is 1018448-65-1.
  • trastuzumab emtansine has been (or is currently being) evaluated in several clinical trials, including NCT00829166 and NCT01772472.
  • Complete information about trastuzumab emtansine preparation, dispensing, dosage, and administration schedule can be found in the local package insert (for the United States, see, e.g., www. accessdata (dot) fda (dot) gov/drugsatfda_docs/label/2019/125427s105lbl. pdf. Further details regarding the structure and synthesis of trastuzumab emtansine are provided in WO 2001/000244A2 and WO 2001/000245A2, the contents of which are incorporated herein by reference in their entireties.
  • the anti-HER2 ADC is trastuzumab deruxtecan (also known as T-DXd, DS8201, DS8201a, and ) , which is under development by Daiichi-Sankyo and AstraZeneca.
  • trastuzumab deruxtecan consists of the humanized monoclonal IgG1 antibody trastuzumab covalently linked to the cytotoxic agent deruxtecan (i.e., a topoisomerase I inhibitor ) through MC-GGFG, a cleavable tetrapeptide linker. See Iwata et al.
  • membrane permeable deruxtecan Upon release from the ADC, membrane permeable deruxtecan causes DNA damage and apoptotic cell death. See Xu et al. (2019) Eur J Med Chem. 183: 111682, doi: 10.1016/j. ejmech. 2019.111682. Trastuzumab deruxtecan is rapidly cleared from systemic circulation (Nagai et al. (2019) Xenobiotica. 49 (9) : 1086-1096, doi: 10.1080/00498254.2018.1531158) .
  • trastuzumab deruxtecan Estimated systemic clearance of trastuzumab deruxtecan is 0.42 L/day, according to a population pharmacokinetic analysis (see www(dot) accessdata (dot) fda (dot) gov/drugsatfda_docs/label/2019/761139s000lbl (dot) pdf) .
  • a schematic of trastuzumab deruxtecan is provided in FIG. 1B.
  • the CAS Registry Number for trastuzumab deruxtecan is 1826843-81-5. Trastuzumab deruxtecan has been (or is currently being) evaluated in several clinical trials, including NCT03523585, NCT03529110, and NCT04644237.
  • trastuzumab deruxtecan preparation, dispensing, dosage, and administration schedule can be found in the local package insert (for the United States, see, e.g., www (dot) accessdata (dot) fda (dot) gov/drugsatfda_docs/label/2019/761139s000lbl (dot) pdf. Further details regarding the structure and synthesis of trastuzumab deruxtecan are provided in WO 2015/074528A1, the contents of which are incorporated herein by reference in their entirety.
  • the anti-HER2 ADC is RC48 (also known as RC48-ADC and disitamab vedotin) , which is under development by Remegen Biosciences and Yantai Rongchang Biological Engineering.
  • RC48 consists of the novel anti-HER2 monoclonal antibody disitamab covalently linked to the cytotoxic agent monomethylauristatin E (MMAE) (i.e., a tubulin polymerization inhibitor ) through a cleavable valine–citrulline (val-cit) dipeptide linker coupled with a self-immolative ⁇ -aminobenzyl (PAB) spacer) .
  • MMAE monomethylauristatin E
  • PAB self-immolative ⁇ -aminobenzyl
  • MMAE molecules are conjugated to every anti-HER2 antibody molecule (Corti et al. (2021) Cancers. 13: 2898, doi: 10 (dot) 3390/cancers1312289) .
  • the half maximal inhibitory concentration of RC48 is ⁇ 0.3 nM.
  • the ADC Following the internalization of RC48 by malignant cells expressing HER2, the ADC’s val-cit linker is cleaved by lysosomal enzymes. Upon release from the ADC, membrane permeable MMAE disrupts microtubule assembly.
  • FIG. 1C The CAS Registry Number for RC48 is 2136633-23-1. RC48 has been, is currently being.
  • NCT05134519, NCT05135715, NCT03507166, NCT04264936, NCT04073602, NCT03809013 and NCT04329429 Complete information about RC48 preparation, dispensing, dosage, and administration schedule can be found in the local package insert (for China, see, e.g., http: //remegen. cn/upload/20210708133607. pdf. Further details regarding the structure and synthesis of RC48 are provided in WO2015115091A1, the contents of which are incorporated herein by reference in their entirety.
  • a method of treating tumor (s) in a subject comprising administering to the subject an effective amount of an agent (e.g., therapeutic agent) that blocks the interaction between CD47 (e.g., hCD47) and SIRP ⁇ (e.g., hSIRP ⁇ ) and an effective amount of an anti-HER2 antibody-drug conjugate (ADC) .
  • an agent e.g., therapeutic agent
  • CD47 e.g., hCD47
  • SIRP ⁇ e.g., hSIRP ⁇
  • ADC anti-HER2 antibody-drug conjugate
  • the tumor (s) have been determined via IHC to have a HER2 score of 1+, 2+, or 3+.
  • the tumor (s) have been determined via IHC to have a HER2 score of 1+ or 2+.
  • the tumor (s) are CD47 + . In some embodiments, the tumor (s) are CD47 + and have been determined via IHC to have a HER2 score of 1+, 2+, or 3+. In some embodiments, the tumor from a cancer selected from the group consisting of lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, cholangiocarcinoma, liver cancer, cervical cancer, endometrial cancer, ovarian cancer, peritoneal cancer, urothelial cancer, bladder cancer, gastric cancer, thyroid cancer, melanoma, breast cancer, head and neck cancer, multiple myeloma, acute myeloid leukemia (AML) , uterine cancer, gastro-esophageal cancer, or rectal adenocarcinoma.
  • AML acute myeloid leukemia
  • the agent that blocks the interaction between CD47 and SIRP ⁇ and the anti-HER2 ADC are administered simultaneously. In some embodiments, the agent that blocks the interaction between CD47 and SIRP ⁇ and the anti-HER2 ADC are administered sequentially. In some embodiments, the agent that blocks the interaction between CD47 and SIRP ⁇ is administered prior to the anti-HER2 ADC. In some embodiments, the anti-HER2 ADC is administered prior to the agent that blocks the interaction between CD47 and SIRP ⁇ .
  • the agent that blocks the interaction between CD47 and SIRP ⁇ is a polypeptide. In some embodiments, the agent that blocks the interaction between CD47 and SIRP ⁇ is an antibody, antibody construct or immunologically active fragment of the antibody or antibody construct. In some embodiments, the agent that blocks the interaction between CD47 and SIRP ⁇ is an anti-CD47 antibody or immunologically active fragment thereof.
  • the anti-CD47 antibody or the immunologically active fragment thereof comprises: (a) a VH domain that comprises (1) a CDR-H1 comprising RAWMN (SEQ ID NO: 5) ; (2) a CDR-H2 comprising RIKRKTDGETTDYAAPVKG (SEQ ID NO: 6) ; (3) a CDR-H3 comprising SNRAFDI (SEQ ID NO: 7) and (b) a VL domain that comprises (1) a CDR-L1 comprising KSSQSVLYAGNNRNYLA (SEQ ID NO: 8) ; (2) a CDR-L2 comprising QASTRAS (SEQ ID NO: 9) ; and (3) a CDR-L3 comprising QQYYTPPLA (SEQ ID NO: 10) .
  • the anti-HER2 ADC is trastuzumab emtansine trastuzumab deruxtecan (DS8201) , or disitamab vedotin (RC48) .
  • a method of treating tumor (s) in a subject comprising administering to the subject an effective amount of an anti-CD47 or the immunologically active fragment thereof comprising: (a) a VH domain that comprises (1) a CDR-H1 comprising RAWMN (SEQ ID NO: 5) ; (2) a CDR-H2 comprising RIKRKTDGETTDYAAPVKG (SEQ ID NO: 6) ; (3) a CDR-H3 comprising SNRAFDI (SEQ ID NO: 7) and (b) a VL domain that comprises (1) a CDR-L1 comprising KSSQSVLYAGNNRNYLA (SEQ ID NO: 8) ; (2) a CDR-L2 comprising QASTRAS (SEQ ID NO: 9) ; and (3) a CDR-L3 comprising QQYYTPPLA (SEQ ID NO: 10) ; and an effective amount of trastuzumab e
  • the tumor (s) have been determined via IHC to have a HER2 score of 1+, 2+. In some embodiments, the tumor (s) have been determined via FISH to be FISH+. In some embodiments, the tumor (s) have been determined via FISH to be FISH-. In some embodiments, the tumor is CD47 + . In some embodiments, the tumor is CD47 + and has been determined via IHC to have a HER2 score of 1+, 2+, or 3+.
  • the tumor is from a cancer selected from the group consisting of lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, cholangiocarcinoma, liver cancer, cervical cancer, endometrial cancer, ovarian cancer, peritoneal cancer, urothelial cancer, bladder cancer, gastric cancer, thyroid cancer, melanoma, breast cancer, head and neck cancer, multiple myeloma, acute myeloid leukemia (AML) , uterine cancer, gastro-esophageal cancer, or rectal adenocarcinoma.
  • the anti-CD47 antibody and the anti-HER2 ADC are administered simultaneously.
  • the anti-CD47 antibody and the anti-HER2 ADC are administered sequentially. In some embodiments, the anti-CD47 antibody is administered prior to the anti-HER2 ADC. In some embodiments, the anti-HER2 ADC is administered prior to the anti-CD47 antibody.
  • a method of treating tumor (s) in a subject comprising administering to the subject an effective amount of an anti-CD47 or the immunologically active fragment thereof comprising: (a) a VH domain that comprises (1) a CDR-H1 comprising RAWMN (SEQ ID NO: 5) ; (2) a CDR-H2 comprising RIKRKTDGETTDYAAPVKG (SEQ ID NO: 6) ; (3) a CDR-H3 comprising SNRAFDI (SEQ ID NO: 7) and (b) a VL domain that comprises (1) a CDR-L1 comprising KSSQSVLYAGNNRNYLA (SEQ ID NO: 8) ; (2) a CDR-L2 comprising QASTRAS (SEQ ID NO: 9) ; and (3) a CDR-L3 comprising QQYYTPPLA (SEQ ID NO: 10) ; and an effective amount of trastuzumab derux
  • the tumor (s) have been determined via IHC to have a HER2 score of 1+, 2+, or 3+. In some embodiments, the tumor (s) have been determined via IHC to have a HER2 score of 1+, 2+. In some embodiments, the tumor (s) have been determined via FISH to be FISH+. In some embodiments, the tumor (s) have been determined via FISH to be FISH-. In some embodiments, the tumor is CD47 + . In some embodiments, the tumor is CD47 + and has been determined via IHC to have a HER2 score of 1+, 2+, or 3+.
  • the tumor is from a cancer selected from the group consisting of lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, cholangiocarcinoma, liver cancer, cervical cancer, endometrial cancer, ovarian cancer, peritoneal cancer, urothelial cancer, bladder cancer, gastric cancer, thyroid cancer, melanoma, breast cancer, head and neck cancer, multiple myeloma, acute myeloid leukemia (AML) , uterine cancer, gastro-esophageal cancer, or rectal adenocarcinoma.
  • the anti-CD47 antibody and the anti-HER2 ADC are administered simultaneously.
  • the anti-CD47 antibody and the anti-HER2 ADC are administered sequentially. In some embodiments, the anti-CD47 antibody is administered prior to the anti-HER2 ADC. In some embodiments, the anti-HER2 ADC is administered prior to the anti-CD47 antibody.
  • a method of treating tumor in a subject comprising administering to the subject an effective amount of an anti-CD47 or the immunologically active fragment thereof comprising: (a) a VH domain that comprises (1) a CDR-H1 comprising RAWMN (SEQ ID NO: 5) ; (2) a CDR-H2 comprising RIKRKTDGETTDYAAPVKG (SEQ ID NO: 6) ; (3) a CDR-H3 comprising SNRAFDI (SEQ ID NO: 7) and (b) a VL domain that comprises (1) a CDR-L1 comprising KSSQSVLYAGNNRNYLA (SEQ ID NO: 8) ; (2) a CDR-L2 comprising QASTRAS (SEQ ID NO: 9) ; and (3) a CDR-L3 comprising QQYYTPPLA (SEQ ID NO: 10) ; and an effective amount of disitamab vedotin (SEQ ID NO: 5) ; and an effective amount of disitamab
  • the tumor (s) have been determined via IHC to have a HER2 score of 1+, 2+, or 3+. In some embodiments, the tumor (s) have been determined via IHC to have a HER2 score of 1+, 2+. In some embodiments, the tumor (s) have been determined via FISH to be FISH+. In some embodiments, the tumor (s) have been determined via FISH to be FISH-. In some embodiments, the tumor is CD47 + . In some embodiments, the tumor is CD47 + and has been determined via IHC to have a HER2 score of 1+, 2+, or 3+.
  • the tumor is from a cancer selected from the group consisting of lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, cholangiocarcinoma, liver cancer, cervical cancer, endometrial cancer, ovarian cancer, peritoneal cancer, urothelial cancer, bladder cancer, gastric cancer, thyroid cancer, melanoma, breast cancer, head and neck cancer, multiple myeloma, acute myeloid leukemia (AML) , uterine cancer, gastro-esophageal cancer, or rectal adenocarcinoma.
  • the anti-CD47 antibody and the anti-HER2 ADC are administered simultaneously.
  • the anti-CD47 antibody and the anti-HER2 ADC are administered sequentially. In some embodiments, the anti-CD47 antibody is administered prior to the anti-HER2 ADC. In some embodiments, the anti-HER2 ADC is administered prior to the anti-CD47 antibody.
  • a method of treating tumor comprising administering to the subject an effective amount of an anti-CD47 antibody comprising (a) V H domain that comprises SEQ ID NO: 1 and (b) a V L domain that comprises SEQ ID NO: 2 and an effective amount of an anti-HER2 ADC.
  • a method of treating tumor comprising administering to the subject an effective amount of an anti-CD47 antibody comprising (a) V H domain that comprises SEQ ID NO: 1 and (b) a V L domain that comprises SEQ ID NO: 2 and an effective amount of trastuzumab emtansine
  • the tumor (s) have been determined via IHC to have a HER2 score of 1+, 2+, or 3+.
  • the tumor (s) have been determined via IHC to have a HER2 score of 1+, 2+.
  • the tumor (s) have been determined via FISH to be FISH+.
  • the tumor have been determined via FISH to be FISH-.
  • the tumor is CD47 + .
  • the tumor is CD47 + and has been determined via IHC to have a HER2 score of 1+, 2+, or 3+.
  • the tumor is from a cancer selected from the group consisting of lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, cholangiocarcinoma, liver cancer, cervical cancer, endometrial cancer, ovarian cancer, peritoneal cancer, urothelial cancer, bladder cancer, gastric cancer, thyroid cancer, melanoma, breast cancer, head and neck cancer, multiple myeloma, acute myeloid leukemia (AML) , uterine cancer, gastro-esophageal cancer, or rectal adenocarcinoma.
  • the anti-CD47 antibody and the anti-HER2 ADC are administered simultaneously.
  • the anti-CD47 antibody and the anti-HER2 ADC are administered sequentially. In some embodiments, the anti-CD47 antibody is administered prior to the anti-HER2 ADC. In some embodiments, the anti-HER2 ADC is administered prior to the anti-CD47 antibody.
  • a method of treating tumor comprising administering to the subject an effective amount of an anti-CD47 antibody comprising (a) V H domain that comprises SEQ ID NO: 1 and (b) a V L domain that comprises SEQ ID NO: 2 and an effective amount of trastuzumab deruxtecan (DS8201) .
  • the tumor (s) have been determined via IHC to have a HER2 score of 1+, 2+, or 3+.
  • the tumor (s) have been determined via IHC to have a HER2 score of 1+, 2+.
  • the tumor (s) have been determined via FISH to be FISH+.
  • the tumor have been determined via FISH to be FISH-.
  • the tumor is CD47 + .
  • the tumor is CD47 + and has been determined via IHC to have a HER2 score of 1+, 2+, or 3+.
  • the tumor is from a cancer selected from the group consisting of lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, cholangiocarcinoma, liver cancer, cervical cancer, endometrial cancer, ovarian cancer, peritoneal cancer, urothelial cancer, bladder cancer, gastric cancer, thyroid cancer, melanoma, breast cancer, head and neck cancer, multiple myeloma, acute myeloid leukemia (AML) , uterine cancer, gastro-esophageal cancer, or rectal adenocarcinoma.
  • the anti-CD47 antibody and the anti-HER2 ADC are administered simultaneously.
  • the anti-CD47 antibody and the anti-HER2 ADC are administered sequentially. In some embodiments, the anti-CD47 antibody is administered prior to the anti-HER2 ADC. In some embodiments, the anti-HER2 ADC is administered prior to the anti-CD47 antibody.
  • a method of treating tumor comprising administering to the subject an effective amount of an anti-CD47 antibody comprising (a) V H domain that comprises SEQ ID NO: 1 and (b) a V L domain that comprises SEQ ID NO: 2 and an effective amount of disitamab vedotin (RC48) .
  • the tumor (s) have been determined via IHC to have a HER2 score of 1+, 2+, or 3+.
  • the tumor (s) have been determined via IHC to have a HER2 score of 1+, 2+.
  • the tumor (s) have been determined via FISH to be FISH+.
  • the tumor have been determined via FISH to be FISH-.
  • the tumor is CD47 + .
  • the tumor is CD47 + and has been determined via IHC to have a HER2 score of 1+, 2+, or 3+.
  • the tumor is from a cancer selected from the group consisting of lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, cholangiocarcinoma, liver cancer, cervical cancer, endometrial cancer, ovarian cancer, peritoneal cancer, urothelial cancer, bladder cancer, gastric cancer, thyroid cancer, melanoma, breast cancer, head and neck cancer, multiple myeloma, acute myeloid leukemia (AML) , uterine cancer, gastro-esophageal cancer, or rectal adenocarcinoma.
  • the anti-CD47 antibody and the anti-HER2 ADC are administered simultaneously.
  • the anti-CD47 antibody and the anti-HER2 ADC are administered sequentially. In some embodiments, the anti-CD47 antibody is administered prior to the anti-HER2 ADC. In some embodiments, the anti-HER2 ADC is administered prior to the anti-CD47 antibody.
  • the agent that blocks the interaction between CD47 (e.g., hCD47) and SIRP ⁇ (e.g., hSIRP ⁇ ) and the anti-HER2 ADC are administered simultaneously.
  • “simultaneous administration” means that the agent that blocks the interaction between CD47 (e.g., hCD47) and SIRP ⁇ (e.g., hSIRP ⁇ ) and the anti-HER2 ADC are administered with a time separation of no more than about 15 minute (s) , such as no more than about any of 10, 5, or 1 minutes.
  • the agent that blocks the interaction between CD47 (e.g., hCD47) and SIRP ⁇ (e.g., hSIRP ⁇ ) and the anti-HER2 ADC are administered sequentially.
  • “sequential administration” means that the agent that blocks the interaction between CD47 (e.g., hCD47) and SIRP ⁇ (e.g., hSIRP ⁇ ) and the anti-HER2 ADC are administered with a time separation of more than about 15 minutes, such as more than about any of 20, 30, 40, 50, 60 or more minutes.
  • the agent that blocks the interaction between CD47 and SIRP ⁇ is administered prior to the anti-HER2 ADC.
  • the anti-HER2 ADC is administered prior to the agent that blocks the interaction between CD47 and SIRP ⁇ . In some embodiments, the administration of the agent that blocks the interaction between CD47 and SIRP ⁇ and the anti-HER2 ADC are concurrent, i.e., the administration period of agent that blocks the interaction between CD47 and SIRP ⁇ and the anti-HER2 ADC overlap with each other. In some embodiments, the administration of the agent that blocks the interaction between CD47 and SIRP ⁇ and the anti-HER2 ADC are non-concurrent.
  • an agent e.g., therapeutic agent
  • CD47 e.g., hCD47
  • SIRP ⁇ e.g., hSIRP ⁇
  • a subject e.g., a human subject
  • the medicament is for administration with an anti-HER2 ADC.
  • an anti-HER2 ADC in the manufacture of a medicament for treating tumor (s) in a subject (e.g., a human subject) , wherein the medicament is for administration with an agent (e.g., therapeutic agent) that blocks the interaction between CD47 (e.g., hCD47) and SIRP ⁇ (e.g., hSIRP ⁇ ) .
  • an agent e.g., therapeutic agent
  • CD47 e.g., hCD47
  • SIRP ⁇ e.g., hSIRP ⁇
  • an agent e.g., therapeutic agent
  • CD47 e.g., hCD47
  • SIRP ⁇ e.g., hSIRP ⁇
  • a method of treating a tumor (s) in a subject e.g., a human subject
  • the agent is for use (e.g., administered) with an anti-HER2 ADC.
  • an anti-HER2 ADC in a method of treating tumor (s) in a subject (e.g., a human subject) , wherein the anti-HER2 ADC is for use (e.g., administered) with an agent (e.g., therapeutic agent) that blocks the interaction between CD47 (e.g., hCD47) and SIRP ⁇ (e.g., hSIRP ⁇ ) .
  • an agent e.g., therapeutic agent
  • CD47 e.g., hCD47
  • SIRP ⁇ e.g., hSIRP ⁇
  • the agent that blocks the interaction between CD47 and SIRP ⁇ is a polypeptide.
  • the agent that blocks the interaction between CD47 and SIRP ⁇ is an antibody, antibody construct, or an immunologically active fragment of the antibody of the antibody construct.
  • the agent that blocks the interaction between CD47 and SIRP ⁇ is an anti-CD47 antibody (or immunologically active fragment thereof) .
  • the anti-CD47 antibody is CC-90002 (also known as INBRX103) , 5F9 (also known as Hu5F9-G4 and magrolimab) , LQ001, HLX24, TI-061, AO-176, SRF-231, IBI-188, IMC-002, SHR-1603, STI-6643, ZL-1201, or an immunologically active fragment of any one of the preceding.
  • the anti-CD47 antibody (or immunologically active fragment thereof) is any anti-CD47 antibody (or immunologically active fragment thereof) described herein.
  • the anti-HER2 ADC is trastuzumab emtansine trastuzumab deruxtecan (DS8201) , or disitamab vedotin (RC48) .
  • the tumor (s) have been determined via IHC to have a HER2 score of 1+, 2+, or 3+. In some embodiments, the tumor (s) have been determined via IHC to have a HER2 score of 1+, 2+. In some embodiments, the tumor (s) have been determined via FISH to be FISH+. In some embodiments, the tumor (s) have been determined via FISH to be FISH-. In some embodiments, the tumor is CD47 + .
  • the tumor is CD47 + and has been determined via IHC to have a HER2 score of 1+, 2+, or 3+.
  • the tumor (s) are from a cancer selected from the group consisting of lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, cholangiocarcinoma, liver cancer, cervical cancer, endometrial cancer, ovarian cancer, peritoneal cancer, urothelial cancer, bladder cancer, gastric cancer, thyroid cancer, melanoma, breast cancer, head and neck cancer, multiple myeloma, acute myeloid leukemia (AML) , uterine cancer, gastro-esophageal cancer, or rectal adenocarcinoma.
  • AML acute myeloid leukemia
  • the agent (e.g., therapeutic agent) that blocks the interaction between CD47 (e.g., hCD47) and SIRP ⁇ (e.g., hSIRP ⁇ ) and the anti-HER2 ADC are administered simultaneously.
  • the agent (e.g., therapeutic agent) that blocks the interaction between CD47 (e.g., hCD47) and SIRP ⁇ (e.g., hSIRP ⁇ ) and the anti-HER2 ADC are administered sequentially.
  • the agent (e.g., therapeutic agent) that blocks the interaction between CD47 (e.g., hCD47) and SIRP ⁇ (e.g., hSIRP ⁇ ) is administered prior to the anti-HER2 ADC.
  • the anti-HER2 ADC is administered prior to the agent (e.g., therapeutic agent) that blocks the interaction between CD47 (e.g., hCD47) and SIRP ⁇ (e.g., hSIRP ⁇ ) .
  • agent e.g., therapeutic agent
  • CD47 e.g., hCD47
  • SIRP ⁇ e.g., hSIRP ⁇
  • composition comprising an effective amount of an agent (e.g., therapeutic agent) that blocks the interaction between CD47 (e.g., hCD47) and SIRP ⁇ (e.g., hSIRP ⁇ ) for use in combination with an effective amount of anti-HER2 antibody drug conjugate (ADC) , e.g., for the treatment of tumor (s) in a subject (e.g., a human subject) .
  • ADC anti-HER2 antibody drug conjugate
  • a pharmaceutical composition for treating tumor (s) in a subject comprising an agent that blocks the interaction between CD47 and SIRP ⁇ and an effective amount of an anti-HER2 ADC
  • the pharmaceutical composition comprises one or more pharmaceutically acceptable carriers.
  • the agent that blocks the interaction between CD47 and SIRP ⁇ is a polypeptide. In some embodiments, the agent that blocks the interaction between CD47 and SIRP ⁇ is an antibody, antibody construct or immunologically active fragment of the antibody or antibody construct. In some embodiments, the agent that blocks the interaction between CD47 and SIRP ⁇ is an anti-CD47 antibody or immunologically active fragment thereof.
  • the anti-CD47 antibody or the immunologically active fragment thereof comprises: (a) a VH domain that comprises (1) a CDR-H1 comprising RAWMN (SEQ ID NO: 5) ; (2) a CDR-H2 comprising RIKRKTDGETTDYAAPVKG (SEQ ID NO: 6) ; (3) a CDR-H3 comprising SNRAFDI (SEQ ID NO: 7) and (b) a VL domain that comprises (1) a CDR-L1 comprising KSSQSVLYAGNNRNYLA (SEQ ID NO: 8) ; (2) a CDR-L2 comprising QASTRAS (SEQ ID NO: 9) ; and (3) a CDR-L3 comprising QQYYTPPLA (SEQ ID NO: 10) .
  • the anti-HER2 ADC is trastuzumab emtansine trastuzumab deruxtecan (DS8201) , or disitamab vedotin (RC48) .
  • a pharmaceutical composition described herein is for use in the treatment of tumor (s) that have been determined via IHC to have a HER2 score of 1+, 2+, or 3+. In some embodiments, a pharmaceutical composition described herein is for use in the treatment of tumor (s) that have been determined via IHC to have a HER2 score of 1+, 2+. In some embodiments, a pharmaceutical composition described herein is for use in the treatment of tumor (s) have been determined via FISH to be FISH+. In some embodiments, a pharmaceutical composition described herein is for use in the treatment of tumor (s) that have been determined via FISH to be FISH-.
  • a pharmaceutical composition described herein is for use in the treatment of tumor (s) that are CD47 + . In some embodiments, a pharmaceutical composition described herein is for use in the treatment of tumor (s) that are CD47 + and have been determined via IHC to have a HER2 score of 1+, 2+, or 3+.
  • the tumor (s) are from a cancer selected from the group consisting of lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, cholangiocarcinoma, liver cancer, cervical cancer, endometrial cancer, ovarian cancer, peritoneal cancer, urothelial cancer, bladder cancer, gastric cancer, thyroid cancer, melanoma, breast cancer, head and neck cancer, multiple myeloma, acute myeloid leukemia (AML) , uterine cancer, gastro-esophageal cancer, or rectal adenocarcinoma.
  • a cancer selected from the group consisting of lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, cholangiocarcinoma, liver cancer, cervical cancer, endometrial cancer, ovarian cancer, peritoneal cancer, urothelial cancer, bladder cancer, gastric cancer, thyroid cancer, melanom
  • an article of manufacture or kit for the treatment of tumor (s) in a subject comprising a therapeutic agent that blocks the interaction between CD47 (e.g., hCD47) and SIRP ⁇ (e.g., hSIRP ⁇ ) .
  • a therapeutic agent that blocks the interaction between CD47 (e.g., hCD47) and SIRP ⁇ (e.g., hSIRP ⁇ ) .
  • such therapeutic agent is a polypeptide, e.g., a polypeptide that binds CD47 (e.g., hCD47) .
  • the polypeptide is or comprises an anti-CD47 antibody, an immunologically active fragment thereof, or an antibody-based construct.
  • the anti-CD47 antibody or immunologically active fragment thereof is an anti-CD47 antibody (or fragment thereof) described herein or a pharmaceutical composition comprising such an anti-CD47 antibody or antibody fragment.
  • the article of manufacture or kit comprises a container containing nucleic acid (s) encoding an anti-CD47 antibody (or an immunologically active fragment thereof) , e.g., an anti-CD47 antibody (or fragment) described herein.
  • the kit includes a cell of cell line that produces an anti-CD47 antibody (or immunologically active fragment thereof) described herein.
  • the kit includes one or more positive controls, for example CD47 (or fragments thereof) or CD47 + cells.
  • the kit includes negative controls, for example a surface or solution that is substantially free of CD47, or a cell that does not express CD47.
  • the manufacture or kit further comprises a label or package insert.
  • the label or package insert indicates that the composition is used in combination with an anti-HER2 ADC for the treatment of the tumor in the subject.
  • the anti-HER2 ADC is selected from the group consisting of trastuzumab emtansine trastuzumab deruxtecan (DS8201) , and disitamab vedotin (RC48) .
  • the label or package insert indicates that the kit is for the treatment of tumor (s) that have been determined via IHC to have a HER2 score of 1+, 2+, or 3+. In some embodiments, the label or package insert indicates that the kit is for the treatment of tumor (s) that have been determined via IHC to have a HER2 score of 1+, 2+. In some embodiments, the label or package insert indicates that the kit is for the treatment of tumor (s) that have been determined via FISH to be FISH+. In some embodiments, the label or package insert indicates that the kit is for the treatment of tumor (s) that been determined via FISH to be FISH-.
  • the label or package insert indicates that the kit is for the treatment of tumor (s) that are CD47 + . In some embodiments, the label or package insert indicates that the kit is for the treatment of tumor (s) that are CD47 + and have been determined via IHC to have a HER2 score of 1+, 2+, or 3+.
  • the tumor (s) are from a cancer selected from the group consisting of lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, cholangiocarcinoma, liver cancer, cervical cancer, endometrial cancer, ovarian cancer, peritoneal cancer, urothelial cancer, bladder cancer, gastric cancer, thyroid cancer, melanoma, breast cancer, head and neck cancer, multiple myeloma, acute myeloid leukemia (AML) , uterine cancer, gastro-esophageal cancer, or rectal adenocarcinoma.
  • a cancer selected from the group consisting of lung cancer, colon adenocarcinoma, colorectal adenocarcinoma, pancreatic cancer, cholangiocarcinoma, liver cancer, cervical cancer, endometrial cancer, ovarian cancer, peritoneal cancer, urothelial cancer, bladder cancer, gastric cancer, thyroid cancer, melanom
  • the manufacture or kit further comprises an anti-HER2 ADC.
  • the anti-HER2 ADC is selected from the group consisting of trastuzumab emtansine trastuzumab deruxtecan (DS8201) , and disitamab vedotin (RC48) .
  • the article of manufacture or kit comprises a container.
  • Suitable containers include, for example, bottles, vials, syringes, IV solution bags, test tubes, etc.
  • the containers may be formed from a variety of materials such as glass or plastic.
  • the article of manufacture or kit may comprise (a) a first container with a composition contained therein, wherein the composition comprises an is an agent that blocks the binding of hCD47 to hSIRP ⁇ (such as an anti-CD47 antibody, or immunologically active fragment thereof, e.g., an anti-CD47 antibody described herein or a fragment thereof) , and (b) a second container with a composition contained therein, wherein the composition comprises an anti-HER2 ADC.
  • Exemplary anti-HER2 ADCs that can be packaged with the kits provided herein include, without limitation, e.g., trastuzumab emtansine trastuzumab deruxtecan (DS8201) , or disitamab vedotin (RC48) .
  • the article of manufacture may further comprise an additional container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI) , phosphate-buffered saline, Ringer's solution, and dextrose solution. It may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.
  • Example 1A Expression levels of HER2 and CD47 in Human Breast Cancer and Human Gastric Cancer Cell Lines
  • HER2 and CD47 expression were evaluated via flow cytometry in human breast cancer cell lines MCF-7, MDA-MB-231, and BT-474, and in the human gastric cancer cell line NCI-N87.
  • MCF-1 cells and MDA-MB-231 cells express low levels of HER2, and BT474 cells and NCI-N87 cells express high levels of HER2.
  • FIG. 4B shows that MCF-7 cells express high levels of CD47, that MDA-MB-231 cells express medium levels of CD47, and that BT474 cells and NCI-N87 cells express low levels of CD47.
  • Example 1B Effects of anti-CD47 antibody in combination with anti-HER2 Antibody-Drug Conjugate (ADC) on cell cytotoxicity and phagocytosis activity in vitro
  • ADC Antibody-Drug Conjugate
  • BT474 expresses high levels of HER2 and low levels of CD47
  • MCF-7 expresses low levels of HER2 and high levels of CD47.
  • Lemzoparlimab (also referred to herein as “TJC4” ) comprises a V H that comprises SEQ ID NO: 1, a V L that comprises SEQ ID NO: 2, and a human IgG4 Fc region that comprises an S228P substitution (EU numbering) .
  • TJC4 was tested in combination with the exemplary anti-HER2 ADCs trastuzumab deruxtecan ( “DS8201” ) and disitamab vedotin ( “RC48” ) .
  • BT474 cells and MCF-7 cells were each co-cultured with PBMCs or macrophages and treated with (a) 0 ⁇ g/ml TJC4 + 0 ⁇ g anti-HER2 ADC; (b) 0 ⁇ g/ml TJC4 + 10 ⁇ g anti-HER2 ADC; (c) 10 ⁇ g/ml TJC4 + 0 ⁇ g anti-HER2 ADC; or (d) 10 ⁇ g/ml TJC4 + 10 ⁇ g anti-HER2 ADC.
  • treatment with 10 ⁇ g/ml single agent TJC4 had no effect on BT474 cytolysis, and treatment with 10 ⁇ g/ml single agent anti-HER2 ADC DS8201 resulted in about 15%BT474 cytolysis.
  • treatment with 10 ⁇ g/ml TJC4 + 10 ⁇ g DS8201 resulted in about 30%BT474 cytolysis, higher than treatment with either TJC4 alone or DS8201 alone.
  • treatment with 10 ⁇ g/ml single agent TJC4 resulted in about 20%cytolysis
  • treatment with 10 ⁇ g/ml single agent DS8201 resulted in about >35%cytolysis.
  • Treatment with 10 ⁇ g/ml TJC4 + 10 ⁇ g DS8201 resulted in about 60%MCF-7 cytolysis, higher than treatment with either TJC4 alone or DS8201 alone.
  • Such results indicate that the treatment with an anti-CD47 antibody and an anti-HER2 ADC enhances cell cytotoxicity, as compared to either agent alone, even in cancer cells that express low levels of HER2.
  • treatment with 10 ⁇ g/ml single agent TJC4 led to about 20%phagocytosis of BT474 cells, and treatment with 10 ⁇ g/ml single agent anti-HER2 ADC RC-48 resulted in about 40%phagocytosis of BT474 cells.
  • treatment with 10 ⁇ g/ml TJC4 + 10 ⁇ g RC-48 resulted in about >40%phagocytosis of BT474.
  • treatment with 10 ⁇ g/ml single agent TJC4 resulted in about 10%phagocytosis
  • treatment with 10 ⁇ g/ml single agent RC-48 resulted in about ⁇ 10%cytolysis.
  • Example 1C Anti-tumor efficacy of anti-CD47 antibody in combination with anti-HER2 Antibody-Drug Conjugate (ADC) in mice bearing human cancer cell-line derived xenografted tumors (CDX)
  • exemplary anti-CD47 antibody of the present application TJC4 in combination with an exemplary anti-HER2 ADC was assessed in mice bearing human cancer cell line-derived xenografted tumors (CDX) or patient-derived xenografted tumors (PDX) .
  • Human MDA-MB-231 breast cancer cells expresses comparatively low level of HER2.
  • MDA-MB-231 cells were cultured in RPMI-1640 medium supplemented with 10%fetal bovine serum at 37°C.
  • CB-17 SCID mice female, age: 6-8 weeks, body weight: 16-22g
  • CB-17 SCID mice female, age: 6-8 weeks, body weight: 16-22g
  • 10 ⁇ g/mL 17 ⁇ -estrogen in drinking water 3 days before tumor inoculation Then, the mice were subcutaneously inoculated to the right back with 1 ⁇ 10 7 MDA-MB-231 cells (resuspended in 0.2 mL DPBS comprising 50%Matrigel.
  • mice 12 days later, when tumor volume reached ⁇ 210 mm 3 , animals were randomly divided into four groups, 8 mice per group, and administered with (a) PBS (control) , (b) trastuzumab deruxtecan ( “DS8201” ) monotherapy (FIG. 2A) or disitamab vedotin ( “RC48” ) monotherapy (FIG. 2B) , (c) TJC4 monotherapy, or (d) TJC4 in combination with DS8201 (FIG. 2A) or RC48 (FIG. 2B) .
  • PBS control
  • trastuzumab deruxtecan “DS8201”
  • RC48 disitamab vedotin
  • TJC4 TJC4 in combination with DS8201 (FIG. 2A) or RC48 (FIG. 2B) .
  • V N is mean tumor volume on day N of administration
  • V 0 is mean tumor volume on day 0 of administration
  • V CN is mean tumor volume in control group on day N of administration
  • V C0 is mean tumor volume in control group on day 0 administration.
  • T/C relative tumor inhibition
  • TRTV treatment group RTV
  • CRTV control group RTV
  • RTV V N /V 1 , where V 1 is the mean tumor volume measured on Day 1 of administration, and V N is the mean tumor volume measured on Day N of administration.
  • mice treated with either TJC4 or DS8201 demonstrated tumor growth inhibition as compared to mice treated with PBS control.
  • tumor growth was further inhibited by the combination of TJC4 and DS8201.
  • mice treated with either TJC4 or RC48 demonstrated tumor growth inhibition as compared to mice treated with PBS control.
  • tumor growth was further inhibited by the combination of TJC4 and RC48.
  • mice bearing human NCI-N87 gastric cancer tumor xenografts and in mice bearing MCF-7 breast cancer tumor xenografts Similar experiments were performed in mice bearing human NCI-N87 gastric cancer tumor xenografts and in mice bearing MCF-7 breast cancer tumor xenografts. As noted in Example 1A, NCI-N87 cells express high levels of HER2 and high levels of CD47, and MCF-7 cells express low levels of HER2 and high levels of CD47. As shown in FIG. 2C, mice bearing NCI-N87 tumor xenografts treated with either TJC4 or DS8201 demonstrated tumor growth inhibition as compared to mice treated with PBS control. In addition, NCI-N87 tumor growth was further inhibited by the combination of TJC4 and DS8201. As shown in FIG.
  • mice bearing MCF-7 tumor xenografts treated with either TJC4 or DS8201 demonstrated tumor growth inhibition as compared to mice treated with PBS control.
  • MCF-7 tumor growth was further inhibited by the combination of TJC4 and DS8201.
  • TJC4 enhances the in vivo anti-tumor activity of an anti-HER2 ADC, even in tumor expressing models expressing low levels of HER2.
  • Tumors cells from mice bearing MDA-MB-231 xenografts were analyzed via flow cytometry to assess whether treatments evaluated in FIG 2A affected the degree of immune cell infiltration into tumor tissue.
  • FIG. 2E the degree of infiltration of MDA-MB-231 tumors by macrophages in mice treated with DS8201 was higher than that in mice treated with vehicle (PBS control) , and the degree of infiltration of MDA-MB-231 tumors by macrophages in mice treated with TJC4 (lemzoparlimab) was higher than that in mice treated with DS8201.
  • FIG. 2F shows that the degree of infiltration of MDA-MB-231 tumors by NK cells was higher in mice treated with TJC4 (lemzoparlimab) than in mice treated with vehicle (PBS control) or with DS8201.
  • FIG. 2G shows that the degree of infiltration of MDA-MB-231 tumors by cytotoxic NK cells was higher in mice treated with TJC4 (lemzoparlimab) than in mice treated with vehicle (PBS control) or with DS8201.
  • mice treated with TJC4 (lemzoparlimab) in combination with DS8201 The degree of infiltration of MDA-MB-231 tumors by NK cells in mice treated with TJC4 (lemzoparlimab) in combination with DS8201 was about the same as in mice treated with single agent TJC4 (lemzoparlimab) .
  • FIG. 2H shows that CD47 expression (left panel) and CD68 expression on tumor cells was higher in mice treated with TJC4 (lemzoparlimab) in combination with DS8201 than in mice treated with vehicle (PBS) , with single agent TJC4 (lemzoparlimab) , or with single agent DS8201.
  • TJC4 enhances HER2-ADC mediated tumor killing by modulating NK cell activity and macrophage activity to increase cytotoxicity and phagocytosis.
  • Example 2 Anti-tumor efficacy of anti-CD47 antibody in combination with anti-HER2 Antibody-Drug Conjugate (ADC) in mice bearing patient-derived xenograft tumor.
  • ADC Antibody-Drug Conjugate
  • exemplary anti-CD47 antibody of the present application TJC4 in combination with exemplary anti-HER2 ADC was assessed in mice bearing patient-derived xenograft tumor (PDX) .
  • patient derived breast cancer cells BRC008 (HER2 2+ and CD47 3+ in IHC test) from YiconMed was inoculated into PDX bearing CB-17 SCID mice.
  • PDX tumor volume reached 500-800 mm 3
  • animals were sacrificed, and the tumor tissue was isolated.
  • mice female, age: 6-8 weeks, body weight: 16-22g
  • mice were treated with 10 ⁇ g/mL 17 ⁇ -estrogen in drinking water 3 days before tumor inoculation. Then, the mice were subcutaneously inoculated to the right back with 2mm ⁇ 2mm ⁇ 2mm PDX tumor isolated from the PDX bearing animal describe above. 12 days later, when tumor volume reached 50-80 mm 3 , animals were randomly divided into four groups, 3 mice per group, and administered with (a) PBS (control) , (b) RC48, (c) TJC4 monotherapy, or (d) TJC4 in combination with RC48.
  • V N is mean tumor volume on day N of administration
  • V 0 is mean tumor volume on day 0 of administration
  • V CN is mean tumor volume in control group on day N of administration
  • V C0 is mean tumor volume in control group on day 0 administration.
  • T/C relative tumor inhibition
  • TRTV treatment group RTV
  • CRTV control group RTV
  • RTV V N /V 1 , where V 1 is the mean tumor volume measured on Day 1 of administration, and V N is the mean tumor volume measured on Day N of administration.
  • mice treated with either TJC4 or RC48 demonstrated tumor growth inhibition as compared to mice treated with PBS control.
  • tumor growth was further inhibited by the combination of TJC4 and RC48.
  • mice bearing other patient-derived tumor xenografts i.e., ST-02-0079 gastric cancer tumors (HER2 3+ and CD47 1+ in IHC test) and BR-05-0419 breast cancer tumors (HER2 1+ and CD47 3+ in IHC test) .
  • ST-02-0079 is considered to be a HER2-high /CD47-low cancer
  • BR-05-0419 is considered to be a HER2-low /CD47 high cancer.
  • mice bearing ST-02-0079 gastric cancer tumors treated with either TJC4 or RC48 demonstrated tumor growth inhibition as compared to ST-02-0079-xenografted mice treated with PBS control.
  • FIG. 3C shows that mice bearing BR-05-0419 breast cancer tumors treated with either TJC4 or RC48 demonstrated tumor growth inhibition as compared to BR-05-0419xenografted mice treated with PBS control. BR-05-0419 tumor growth was further inhibited by the combination of TJC4 and RC48, as compared to treatment with either single agent TJC4 or single agent RC48.
  • the results of these PDX experiments indicate that TJC4 enhances the anti-tumor efficacy of an anti-HER2 ADC, even in cancers that express low levels of HER2.

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Abstract

L'invention concerne des méthodes de traitement d'un cancer chez un sujet, comprenant l'administration au sujet d'une quantité efficace d'un agent qui bloque l'interaction entre CD47 et SIRPα (par exemple, un anticorps anti-CD47) et une quantité efficace d'un conjugué anticorps anti-HER2-médicament. L'invention concerne également des kits associés.
PCT/CN2023/085380 2022-03-31 2023-03-31 Polythérapies comprenant un conjugué anticorps anti-her2-médicament pour le traitement du cancer Ceased WO2023186067A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017121771A1 (fr) * 2016-01-11 2017-07-20 Blink Biomedical Sas Anticorps monoclonaux anti-cd47 humanisés, de souris ou chimériques
WO2018075857A1 (fr) * 2016-10-20 2018-04-26 I-Mab Nouveaux anticorps monoclonaux anti-cd 47 et leurs utilisations
WO2021219092A1 (fr) * 2020-04-30 2021-11-04 I-Mab Biopharma Co., Ltd. Compositions pharmaceutiques contenant des anticorps anti-cd47

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017121771A1 (fr) * 2016-01-11 2017-07-20 Blink Biomedical Sas Anticorps monoclonaux anti-cd47 humanisés, de souris ou chimériques
WO2018075857A1 (fr) * 2016-10-20 2018-04-26 I-Mab Nouveaux anticorps monoclonaux anti-cd 47 et leurs utilisations
WO2021219092A1 (fr) * 2020-04-30 2021-11-04 I-Mab Biopharma Co., Ltd. Compositions pharmaceutiques contenant des anticorps anti-cd47

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Title
CHENG HSIN YUAN, YI MICHAEL, BETHUNE MICHAEL, GSCHWENG ERIC, AU MELINDA, NGUYEN DUY, ZHANG KRISTEN, SHENOY TANU, SASU BARBRA, BLAR: "Generation of hypoimmunogenic allogeneic CAR T cells by inactivation of transcriptional regulators of HLA Class I and II genes", JOURNAL FOR IMMUNOTHERAPY OF CANCER, BIOMED CENTRAL, LONDON, GB, vol. 10, no. Suppl. 2, 7 November 2022 (2022-11-07), GB , pages A224, XP093094666, ISSN: 2051-1426, DOI: 10.1136/jitc-2022-SITC2022.0210 *
MUSOLINO ANTONINO, GRADISHAR WILLIAM J, RUGO HOPE S, NORDSTROM JEFFREY L, ROCK EDWIN P, ARNALDEZ FERNANDA, PEGRAM MARK D: "Role of Fcγ receptors in HER2-targeted breast cancer therapy", JOURNAL FOR IMMUNOTHERAPY OF CANCER, vol. 10, no. 1, 1 January 2022 (2022-01-01), pages e003171, XP093096648, DOI: 10.1136/jitc-2021-003171 *
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