WO2024052830A1

WO2024052830A1 - Treatment regimens with anti-cd47 / anti-pd-l1 bispecific antibodies

Info

Publication number: WO2024052830A1
Application number: PCT/IB2023/058819
Authority: WO
Inventors: Loleta Delaine HARRIS; Jonathan Ryan Richard HEYEN; Kenneth Alan KERN; Jingwen Zheng
Original assignee: Pfizer Inc.
Priority date: 2022-09-09
Filing date: 2023-09-06
Publication date: 2024-03-14

Abstract

The present disclosure provides dosing regimens for the treatment of patients with cancer with an anti-CD47 / anti-PD-L1 bispecific antibody. The present disclosure further provides methods for the treatment of patients with cancer in which an anti- CD47 / anti-PD-L1 bispecific antibody is administered by subcutaneous injection or infusion.

Description

TREATMENT REGIMENS WITH ANTI-CD47 / ANTI-PD-L1 BISPECIFIC ANTIBODIES

BACKGROUND

The present invention relates to therapeutic regimens for treatment of patients with cancer. The therapeutic regimens involve administration of an anti-CD47 / anti- PD-L1 bispecific antibody to patients in need thereof.

Anti-CD47 / anti-PD-L1 bispecific antibodies are described in, for example, WO2021/124073 (published 24 June 2021 ).

There remains a significant clinical need for further cancer therapies using anti- CD47 / anti-PD-L1 bispecific antibodies.

SUMMARY

The present invention provides dosing regimens for the treatment of cancer with anti-CD47 / anti-PD-L1 bispecific antibodies.

In some embodiments, provided herein is a method for the treatment of a patient having cancer, comprising administering to the patient an effective amount of an anti-CD47 / anti-PD-L1 bispecific antibody, wherein the antibody is administered at least twice every week, at least weekly (QW), at least every 2 weeks (Q2W), at least every 3 weeks (Q3W) or at least every 4 weeks (Q4W).

In some embodiments, provided herein is a method for the treatment of a patient having cancer, comprising administering to the patient an effective amount of an anti-CD47 / anti-PD-L1 bispecific antibody, and wherein the antibody is administered SC at a dose of about 150, 450, 900, 1200, 1800, 2400, or 3600 mg every two weeks (Q2W).

In some embodiments, provided herein is a method for the treatment of a patient having cancer, comprising administering to the patient an effective amount of an anti-CD47 / anti-PD-L1 bispecific antibody, wherein between 1200 mg - 2400 mg of an anti-CD47 I anti-PD-L1 bispecific antibody is administered to a patient via subcutaneous infusion, wherein the anti-CD47 / anti-PD-L1 bispecific antibody is in a liquid pharmaceutical composition that contains between 140 mg/ml - 200 mg/ml anti- CD47 / anti-PD-L1 bispecific antibody, wherein the volume of anti-CD47 / anti-PD-L1 bispecific antibody-containing liquid pharmaceutical composition administered to the patient is between 8 ml - 24 ml, and wherein the anti-CD47 / anti-PD-L1 -containing liquid pharmaceutical composition is administered to the patient at a rate of between 8 ml / hour - 20 ml / hour.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides an exemplary clinical study design for dose escalation and expansion of the anti-CD47 / anti-PD-L1 bispecific antibody PF-07257876.

DETAILED DESCRIPTION

The present disclosure provides dosing regimens for the treatment of cancer with an anti-CD47 I anti-PD-L1 bispecific antibody or a pharmaceutical composition comprising the same.

The present invention may be understood more readily by reference to the following detailed description of the embodiments of the invention and the Examples included herein. It is to be understood that this invention is not limited to specific methods of making that may of course vary. It is to be also understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to be limiting.

Exemplary embodiments (E) of the invention provided herein include:

E1. A method for the treatment of a patient having cancer, comprising administering to the patient an effective amount of an anti-CD47 I anti-PD-L1 bispecific antibody, wherein the antibody is administered at least twice every week, at least weekly (QW), at least every 2 weeks (Q2W), at least every 3 weeks (Q3W) or at least every 4 weeks (Q4W).

E2. The method of E1 , wherein the antibody is administered Q2W.

E3. The method of any one of E1-E2, wherein the antibody is administered subcutaneously (SC), intravenously (IV), intramuscularly, by bolus injection, intracerebrally, or by sustained release.

E4. The method of any one of E1-E3, wherein the antibody is administered at a dose of about 100-3600 mg, about 100-1200 mg, about 450-1200 mg, about 600-1200 mg, about 700-1200 mg, 800-1200 mg, about 900-1200 mg, about 600-1800 mg, about 600-2400, or about 600-3600 mg. E5. The method of any one of E1-E4, wherein the antibody is administered at a dose between a) a lower level of 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000, 1010, 1020, 1030, 1040, 1050, 1060, 1070, 1080, 1090, 1100, 1110, 1120, 1130, 1140, 1150, 1160, 1170, 1180, 1190, 1200, 1210, 1220, 1230, 1240, 1250, 1260, 1270, 1280, 1290, or 1300 mg, and b) an upper level of 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000, 1010, 1020, 1030, 1040, 1050, 1060, 1070, 1080, 1090, 1100, 1110, 1120, 1130, 1140, 1150, 1160, 1170, 1180,

1190, 1200, 1210, 1220, 1230, 1240, 1250, 1260, 1270, 1280, 1290, 1300, 1310,

1320, 1330, 1340, 1350, 1360, 1370, 1380, 1390, 1400, 1410, 1420, 1430, 1440,

1450, 1460, 1470, 1480, 1490, 1500, 1510, 1520, 1530, 1540, 1550, 1560, 1570,

1580, 1590, 1600, 1610, 1620, 1630, 1640, 1650, 1660, 1670, 1680, 1690, 1700,

1710, 1720, 1730, 1740, 1750, 1760, 1770, 1780, 1790, 1800, 1810, 1820, 1830,

1840, 1850, 1860, 1870, 1880, 1890, 1900, 1910, 1920, 1930, 1940, 1950, 1960,

1970, 1980, 1990, 2000, 2010, 2020, 2030, 2040, 2050, 2060, 2070, 2080, 2090,

2100, 2110, 2120, 2130, 2140, 2150, 2160, 2170, 2180, 2290, 2300, 2310, 2320,

2330, 2340, 2350, 2360, 2370, 2380, 2390, 2400, 2410, 2420, 2430, 2440, 2450,

2460, 2470, 2480, 2490, or 2500 mg, wherein the lower level is a smaller value than the upper level.

E6. The method of any one of E1-E5, wherein the antibody is administered SC at a dose of about 150-3600 mg.

E7. The method of any one of E1-E6, wherein the antibody is administered SC at a dose of about 150, 450, 900, 1200, 1800, 2400, or 3600 mg.

E8. A method for the treatment of a patient having cancer, comprising administering to the patient an effective amount of an anti-CD47 I anti-PD-L1 bispecific antibody, and wherein the antibody is administered SC at a dose of about 150, 450, 900, 1200, 1800, 2400, or 3600 mg every two weeks (Q2W).

E9. The method of any one of E1-E8, wherein the antibody is formulated in a pharmaceutical composition. E10. The method of E9, wherein the pharmaceutical composition comprises 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, or 200 mg antibody I ml.

E11. The method of any one of E8-E9, wherein the pharmaceutical composition is administered as one or more boluses by SC injection, or as an infusion by SC infusion.

E12. The method of E11 , wherein 1200 mg or more of the antibody is administered, and the pharmaceutical composition is administered as an infusion by SC infusion.

E13. The method of E12, wherein the pharmaceutical composition is administered at a rate between 8 ml - 20 ml per hour.

E14. The method of any one of E12 or E13, wherein between 8 ml - 24 ml of the pharmaceutical composition is administered to the patient.

E15. A method for the treatment of a patient having cancer, comprising administering to the patient an effective amount of an anti-CD47 I anti-PD-L1 bispecific antibody, wherein between 1200 mg - 2400 mg of an anti-CD47 / anti-PD-L1 bispecific antibody is administered to a patient via subcutaneous infusion, wherein the anti-CD47 I anti- PD-L1 bispecific antibody is in a liquid pharmaceutical composition that contains between 140 mg/ml - 200 mg/ml anti-CD47 / anti-PD-L1 bispecific antibody, wherein the volume of anti-CD47 / anti-PD-L1 bispecific antibody-containing liquid pharmaceutical composition administered to the patient is between 8 ml - 24 ml, and wherein the anti-CD47 / anti-PD-L1 -containing liquid pharmaceutical composition is administered to the patient at a rate of at between 8 ml / hour - 20 ml / hour.

E16. The method of any one of E1 -E15, wherein the bispecific antibody comprises a first antigen binding portion that binds to CD47 and a second antigen binding portion that binds to PD-L1 , wherein the first antigen binding portion comprises a VH and a VL, wherein the second antigen binding portion comprises a VH and a VL, and wherein: a) the first antigen binding portion VH comprises (i) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1 , 2, or 3; (ii) a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 4 or 5; and (iii) a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 6; b) the first antigen binding portion VL comprises (i) a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 7; (ii) a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 8; and (iii) a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 9; c) the second antigen binding portion VH comprises (i) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 14, 15, or 16; (ii) a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 17 or 18; and (iii) a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 19; and d) the second antigen binding portion VL comprises (i) a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 7; (ii) a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 8; and (iii) a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 9.

E17. The method of E16, wherein the first antigen binding portion VH comprises the amino acid sequence as shown in SEQ ID NO: 10, the first antigen binding portion VL comprises the amino acid sequence as shown in SEQ ID NO: 11 , the second antigen binding portion VH comprises the amino acid sequence as shown in SEQ ID NO: 20, and the second antigen binding portion VL comprises the amino acid sequence as shown in SEQ ID NO: 11 .

E18. The method of any one of E1-E17, wherein the antibody comprises an anti-CD47 heavy chain comprising the amino acid sequence of SEQ ID NO: 12 and the antibody comprises an anti-PD-L1 heavy chain comprising the amino acid sequence of SEQ ID NO: 21.

E19. The method of E18, wherein the antibody further comprises an anti-CD47 light chain comprising the amino acid sequence of SEQ ID NO: 13 and an anti-PD-L1 light chain comprising the amino acid sequence of SEQ ID NO: 13.

E20. The method of any one of E1 -E19, wherein the antibody comprises a first antibody heavy chain, a second antibody heavy chain, a first antibody light chain, and a second antibody light chain; wherein the first antibody heavy chain comprises the amino acid sequence of SEQ ID NO: 12 and the second antibody heavy chain comprises the amino acid sequence of SEQ ID NO: 21 ; and wherein both the first antibody light chain and the second antibody light chain comprise the amino acid sequence of SEQ ID NO: 13. E21. The method of any one of E1 -E20, wherein the affinity of the anti-PD-L1 antigen binding portion for PD-L1 is greater than the affinity of the anti-CD47 antigen binding portion for CD47.

E22. The method of any one of E1 -E21 , wherein the cancer is non-small cell lung cancer (NSCLC), optionally adenocarcinoma NSCLC, squamous cell carcinoma of the head and neck (SCCHN), renal cell carcinoma (RCC), urothelial carcinoma (UC), melanoma, ovarian cancer, or colorectal cancer (CRC).

E23. The method of E22, wherein a) the CRC is microsatellite stable CRC (MSSCRC), optionally further wherein the MSS CRC is anti-PD-1 / PD-L1 treatment naive, b) the NSCLC, SCCHN, RCC, UC, or melanoma is anti-PD-1 I PD-L1 treatment resistant, or c) the ovarian cancer is anti-PD-1 treatment naive.

E24. The method of any one of E1 -E23, wherein the treatment results in a decrease in tumor size of at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% as compared to the tumor size in the patient prior to first administration of the bispecific antibody.

E25. The method of any one of E1 -E24, wherein the patient is a human.

E26. An anti-CD47 I anti-PD-L1 bispecific antibody for use in treatment of a patient having cancer according to a method as recited in any one of E1 -E25.

E27. Use of an anti-CD47 I anti-PD-L1 bispecific antibody for treatment of cancer according to any one of E1 -E25.

E28. Use of an anti-CD47 I anti-PD-L1 bispecific antibody for the preparation of a medicament for treatment of cancer according to any one of E1 -E25.

General Techniques

The practice of the present invention will employ, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry and immunology, which are within the skill of the art. Such techniques are explained fully in the literature, such as, Molecular Cloning: A Laboratory Manual, second edition (Sambrook et al., 1989) Cold Spring Harbor Press; Oligonucleotide Synthesis (M. J. Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (J.E. Gellis, ed., 1998) Academic Press; Animal Cell Culture (RL Freshney, ed., 1987); Introduction to Cell and Tissue Culture (J.P. Mather and P.E. Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A. Doyle, J. B. Griffiths, and D.G. Newell, eds., 1993-1998) J. Wiley and Sons; Methods in Enzymology (Academic Press, Inc.); Handbook of Experimental Immunology (D.M. Weir and C.C. Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (J.M. Miller and M.P. Calos, eds., 1987); Current Protocols in Molecular Biology (F.M. Ausubel et al., eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994); Current Protocols in Immunology (J.E. Coligan et al., eds., 1991 ); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (C.A. Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: a practical approach (D. Catty., ed., IRL Press, 1988-1989); Monoclonal antibodies: a practical approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using antibodies: a laboratory manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and J.D. Capra, eds. Harwood Academic Publishers, 1995).

An “antibody” or “Ab” is an immunoglobulin molecule capable of recognizing and binding to a specific target or antigen, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least one antigen recognition site, located in the variable region of the immunoglobulin molecule. As used herein, the term “antibody” encompasses any type of antibody, including but not limited to monoclonal antibodies, polyclonal antibodies, antigen-binding fragments (or portion), such as Fab, Fab’, F(ab’)2, Fd, Fv, Fc, etc., of intact antibodies that retain the ability to specifically bind to a given antigen (e.g. PD-L1 ), an isolated complementarity determining region (CDR), bispecific antibodies, heteroconjugate antibodies, mutants thereof, fusion proteins having an antibody, or antigen-binding fragment thereof, (e.g., a domain antibody), single chain (ScFv) and single domain antibodies (e.g., shark and camelid antibodies), maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv (see, e.g., Holliger and Hudson, 2005, Nature Biotechnology 23(9): 1126- 1136), humanized antibodies, chimeric antibodies and any other modified configuration of the immunoglobulin molecule that includes an antigen recognition site of the required specificity, including glycosylation variants of antibodies, amino acid sequence variants of antibodies, and covalently modified antibodies. The antibodies may be of murine, rat, human, or any other origin (including chimeric or humanized antibodies). In some aspects of the invention, the antibody, or antigen-binding fragment thereof, binds to CD47 and PD-L1

A “variable region” of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination. As known in the art, the variable regions of the heavy and light chain each consist of four framework regions (FR) connected by three complementarity determining regions (CDRs) also known as hypervariable regions. The CDRs in each chain are held together in close proximity by the FRs and, with the CDRs from the other chain, contribute to the formation of the antigen binding site of antibodies. There are at least two techniques for determining CDRs: (1 ) an approach based on crossspecies sequence variability (i.e., Kabat et al. Sequences of Proteins of Immunological Interest, (5th ed., 1991 , National Institutes of Health, Bethesda MD)); and (2) an approach based on crystallographic studies of antigen-antibody complexes (Al- Lazikani et al., J. Molec. Biol. 273:927-948 (1997)). As used herein, a CDR may refer to CDRs defined by either approach or by a combination of both approaches.

A CDR of a variable domain are comprised of amino acid residues within the variable region that are identified in accordance with the definitions of Kabat, Chothia, the accumulation of both Kabat and Chothia, VBASE2, AbM, contact, and/or conformational definitions or any method of CDR determination well known in the art. Antibody CDRs may be identified as the hypervariable regions originally defined by Kabat et al. See, e.g., Kabat et al., 1992, Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, NIH, Washington D.C. The positions of the CDRs may also be identified as the structural loop structures originally described by Chothia and others. See, e.g., Chothia et al., Nature 342:877-883, (1989). The CDR positions may also be derived from an analysis of the VBASE2 database. (See, e.g. Retter et al., Nucleic Acids Res. 33(Database Issue): D671 -D674, 2005).

Other approaches to CDR identification include the “AbM definition,” which is a compromise between Kabat and Chothia and is derived using Oxford Molecular's AbM antibody modeling software (now ACCELRYS®), or the “contact definition” of CDRs based on observed antigen contacts, set forth in MacCallum et al., J. Mol. Biol., 262:732-745, (1996). In another approach, referred to herein as the “conformational definition” of CDRs, the positions of the CDRs may be identified as the residues that make enthalpic contributions to antigen binding. See, e.g., Makabe et al., Journal of Biological Chemistry, 283:1156-1166, 2008. Still other CD R boundary definitions may not strictly follow one of the above approaches, but will nonetheless overlap with at least a portion of the Kabat CDRs, although they may be shortened or lengthened in light of prediction or experimental findings that particular residues or groups of residues or even entire CDRs do not significantly impact antigen binding. As used herein, a CDR may refer to CDRs defined by any approach known in the art, including combinations of approaches. The methods used herein may utilize CDRs defined according to any of these approaches. For anti-CD47 and anti-PD-L1 antibodies described herein, CDRs may be defined in accordance with any of Kabat, Chothia, extended, VBASE2, AbM, contact, and/or conformational definitions.

Antibodies, antibody domains, and antigen-binding fragments thereof may be described as “polypeptides”, “oligopeptides”, “peptides” and “proteins”, i.e., chains of amino acids of any length. The chain may be linear or branched, it may comprise modified amino acids, and/or may be interrupted by non-amino acids. The terms also encompass an amino acid chain that has been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component. Also included within the definition are, for example, polypeptides containing one or more analogs of an amino acid (including, for example, unnatural amino acids, etc.), as well as other modifications known in the art. It is understood that the polypeptides can occur as single chains or associated chains. Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Commission on Biochemical Nomenclature.

As used herein, the term "dosing regimen" refers to the course of treatment administered to a patient, e.g., treatment with an anti-CD47 I anti-PD-L1 bispecific antibody.

As used herein, the phrases “effective amount” or “effective dosage” are used interchangeably and refer to an amount of a drug (e.g., an anti-CD47 I anti-PD-L1 bispecific antibody), compound, or pharmaceutical composition necessary to achieve one or more beneficial or desired prophylactic or therapeutic results. For prophylactic use, beneficial or desired results include eliminating or reducing the risk of developing a disease (e.g., cancer), delaying the onset of the disease, or preventing the progression of the disease. For therapeutic use, beneficial or desired results include eliminating, reducing the incidence of, or ameliorating one or more symptoms of, these diseases or conditions. Determination of an effective amount or dosage may include observing or measuring changes in biochemical or histological markers; behavioral symptoms of the disease; complications of the disease; and intermediate pathological phenotypes presenting during development of the disease. Determination of an effective amount or dosage may also include observing or measuring a decrease in the dose of another drug/medication required to treat the disease; or an increase in the efficacy of another drug/medication. In particular aspects of the invention, the efficacy of treatment may be determined by measuring the decrease in tumor size as compared to the tumor size in the patient prior to the initial administration of the anti- CD47 / anti-PD-L1 bispecific antibody using methods known in the art (e.g., Response Evaluation Criteria In Solid Tumors (RECIST)). For example, the tumor may decrease in size by at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or up to 100% or up to a point at which the tumor is no longer detectable.

As used herein, the terms "individual", "subject", and “patient” are used interchangeably and refer to a mammal, including, but not limited to, humans, nonhuman primates, horses, dogs, cats, mice, and rats. In a preferred aspect of the invention, the mammal is a human.

As used herein, the terms "pharmaceutically acceptable carrier" and "pharmaceutical acceptable excipient" are used interchangeably and refer to any material which, when combined with an active ingredient, allows the ingredient to retain biological activity and is non-reactive with the patient's immune system. Examples include standard pharmaceutical carriers such as a phosphate buffered saline solution, water, emulsions such as oil/water emulsion, and various types of wetting agents. Compositions comprising such carriers are formulated by well-known conventional methods (see, for example, Remington's Pharmaceutical Sciences, 18^th edition, A. Gennaro, ed., Mack Publishing Co., Easton, PA, 1990; and Remington, The Science and Practice of Pharmacy, 20th Ed., Mack Publishing, 2000). Reference to "about" a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. For example, description referring to "about X" includes description of "X." Numeric ranges are inclusive of the numbers defining the range.

It is understood that wherever embodiments are described herein with the language "comprising," otherwise analogous embodiments described in terms of "consisting of and/or "consisting essentially of are also provided.

Additional scientific and technical terms used in connection with the present invention, unless indicated otherwise herein, shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Generally, nomenclature used in connection with, and techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics, and protein and nucleic acid chemistry and hybridization described herein are those well- known and commonly used in the art.

Anti-CD47 / anti-PD-L 1 bispecific antibodies

The invention can be practiced using, for example, an anti-CD47 / anti-PD-L1 bispecific antibody.

In some embodiments, an anti-CD47 / anti-PD-L1 bispecific antibody used with methods and other aspects provided herein is the molecule PF-07257876.

PF-07257876 is a bispecific antibody that contains a CD47-binding portion and a PD-L1 binding portion. The CD47-binding portion and PD-L1 binding portion each contain a heavy chain and light chain. The light chain for both portions has the same amino acid sequence; it is a common light chain. Having the same light chain sequence for both the CD47-binding and the PD-L1 -binding portion has benefits such as simplifying the manufacture of the PF-07257876 molecule.

Amino acid sequences for various portions of the PF-07257876 molecule are provided below in Table 1.

Table 1 : Amino acid sequences of PF-07257876

In one aspect, the PF-07257876 bispecific antibody is designed to overcome the tumor exposure limitations of existing monospecific CD47 antibodies. The bispecific antibody contains a high affinity PD-L1 binding arm along with a reduced affinity CD47 binding arm (compared with monospecific CD47 antibodies) constructed in an lgG1 format. Given its enhanced affinity for PD-L1 and lower affinity for CD47, PF-07257876 is expected to preferentially bind cells expressing PD-L1 in the tumor, reducing the binding to PD-L1 -negative circulating RBCs (which express CD47). This is intended to increase tumor exposure of the PF-07257876 bispecific antibody and decrease the risk of anemia. Hence, the bispecific approach proposes to maximize the ability to activate antitumor immunity by blocking both innate (CD47 I SIRPa) and adaptive (PD-1 I PD-L1) checkpoints, thus increasing patient safety.

Preclinical data with a murine surrogate of PF-07257876 have shown that the bispecific approach results in enhanced tumor penetration and antitumor activity in murine models via binding to both tumor cells and myeloid cells in the tumor microenvironment. Bispecific blocking of both CD47 and PD-L1 induces distinct activation of macrophage and dendritic cells together with increased stem-like/effector T cells, compared with combination treatment with monospecific anti-CD47 and anti- PD-L1 antibodies.

In some embodiments, methods provided herein are performed with a bispecific antibody comprising a first antigen binding portion that binds to CD47 and a second antigen binding portion that binds to PD-L1 , wherein the first antigen binding portion comprises a VH and a VL, wherein the second antigen binding portion comprises a VH and a VL, and wherein: A) the first antigen binding portion VH comprises (i) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1 , 2, or 3; (ii) a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 4 or 5; and (iii) a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 6; B) the first antigen binding portion VL comprises (i) a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 7; (ii) a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 8; and (iii) a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 9; C) the second antigen binding portion VH comprises (i) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 14, 15, or 16; (ii) a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 17 or 18; and (iii) a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 19; and D) the second antigen binding portion VL comprises (i) a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 7; (ii) a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 8; and (iii) a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 9.

In some aspects, an anti-CD47 I anti-PD-L1 bispecific antibody used with embodiments provided herein can have any of the characteristics of an anti-CD47 I anti-PD-L1 bispecific antibody as described in International Publication Number WQ2021/124073 (published 24 June 2021 ), which is hereby incorporated by reference for all purposes.

Dosing Regimens

The present invention provides for dosing levels, dosing regimens, and methods for the treatment of patients with cancer with an anti-CD47 / anti-PD-L1 bispecific antibody. The present invention further provides for dosing levels, dosing regimens, and methods for the treatment of patients with cancer in which an anti-CD47 I anti-PD-L1 bispecific antibody is administered to a patient intravenously, subcutaneously, intramuscularly, by bolus injection, infusion, intracerebrally or by sustained release. For example, the anti-CD47 I anti-PD-L1 bispecific antibody may be administered by subcutaneous injection or subcutaneous infusion. The present invention further provides for dosing levels, dosing regimens and methods for the treatment of patients with cancer in which an anti-CD47 / anti-PD-L1 bispecific antibody administered to a patient at least twice every week, at least weekly (QW), at least every 2 weeks (Q2W), at least every 3 weeks (Q3W) or at least every 4 weeks (Q4W). The present invention further provides for dosing levels, dosing regimens and methods for the treatment of patients with cancer in which an anti-CD47 / anti-PD-L1 bispecific antibody is administered to a patient intravenously every 2 weeks (Q2W). The anti-CD47 I anti-PD-L1 bispecific antibody may be administered as an initial treatment, or for treatment of cancers that are unresponsive to conventional therapies.

In some embodiments, an anti-CD47 / anti-PD-L1 bispecific antibody is administered at a dose of 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400,

1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, 2000, 2050,

2100, 2150, 2200, 2250, 2300, 2350, 2400, 2450, 2500, 2550, 2600, 2650, 2700,

2750, 2800, 2850, 2900, 2950, 3000, 3050, 3100, 3150, 3200, 3250, 3300, 3350,

3400, 3450, 3500, 3550, or 3600 mg. Optionally, the dose is a flat (also referred to as a “fixed”) dose - i.e. the dose is the amount per patient, and the dose does not depend on the mass of the patient. In some embodiments, the dose is administered to a patient weekly (QW), every 2 weeks (Q2W), or every 3 weeks (Q3W).

In some embodiments, an anti-CD47 / anti-PD-L1 bispecific antibody is administered at a dose between a) a lower level of 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700, 1750, 1800, 1850, 1900, 1950, 2000, 2050, 2100, 2150, or 2200 mg and b) an upper level of 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350, 1400, 1450, 1500, 1550, 1600, 1650, 1700,

1750, 1800, 1850, 1900, 1950, 2000, 2050, 2100, 2150, 2200, 2250, 2300, 2350,

2400, 2450, 2500, 2550, 2600, 2650, 2700, 2750, 2800, 2850, 2900, 2950, 3000,

3050, 3100, 3150, 3200, 3250, 3300, 3350, 3400, 3450, 3500, 3550, or 3600 mg, wherein the lower level is a smaller value than the upper level.

In some embodiments, a dose of an anti-CD47 / anti-PD-L1 bispecific antibody provided herein is administered by subcutaneous infusion. Subcutaneous infusion (also referred to as “hypoderm oclysis”) is a technique in which liquids are infused into one or more subcutaneous sites on a patient. For example, an anti-CD47 / anti-PD-L1 bispecific antibody-containing liquid pharmaceutical composition may be subcutaneously infused at one or more sites on a patient’s abdomen, thighs, back, or arms. Typically, the liquid is infused via a small-gauge needle. The anti-CD47 I anti- PD-L1 bispecific antibody-containing liquid pharmaceutical composition may be subcutaneously infused via an infusion pump. Infusion pumps are commercially available, and include, for example, the BodyGuard (BD), CADD (Smiths Medical), and Sapphire™ (Eitan Medical) families of pumps.

In some embodiments, an anti-CD47 / anti-PD-L1 bispecific antibodycontaining liquid pharmaceutical composition may be subcutaneously infused into a patient at a rate of at least 5 ml I hour, at least 10 ml / hour, at least 15 ml / hour, or at least 20 ml / hour. In some embodiments, an anti-CD47 / anti-PD-L1 bispecific antibody-containing liquid pharmaceutical composition may be subcutaneously infused into a patient at a rate between 5 ml I hour and 20 ml I hour, between 5 ml I hour and 15 ml / hour, or between 10 ml / hour and 20 ml / hour.

In some embodiments, the volume of an anti-CD47 / anti-PD-L1 bispecific antibody-containing liquid pharmaceutical composition subcutaneously infused into a patient is at least 5 ml, 6 ml, 7 ml, 8 ml, 9 ml, 10 ml, 11 ml, 12 ml, 13 ml, 14 ml, 15 ml, 16 ml, 17 ml, 18 ml, 19 ml, 20 ml, 21 ml, 22 ml, 23 ml, 24 ml, 25 ml, 26 ml, 27 ml, 28 ml, 29 ml, or 30 ml. In some embodiments, the volume of an anti-CD47 / anti-PD-L1 bispecific antibody-containing liquid pharmaceutical composition subcutaneously infused into a patient is between 8 ml and 16 ml, between 10 ml and 16 ml, between 12 ml and 16 ml, between 14 ml and 16 ml, between 8 ml and 20 ml, between 10 ml and 20 ml, between 12 ml and 20 ml, between 14 ml and 20 ml, between 8 ml and 24 ml, between 10 ml and 24 ml, between 12 ml and 24 ml, between 14 ml and 24 ml, between 16 ml and 24 ml, or between 20 ml and 24 ml.

In some embodiments, at least 1200 mg of an anti-CD47 / anti-PD-L1 bispecific antibody is administered to a patient via subcutaneous infusion, wherein the anti-CD47 / anti-PD-L1 bispecific antibody is in a liquid pharmaceutical composition that contains between 140 mg/ml - 200 mg/ml anti-CD47 / anti-PD-L1 bispecific antibody, wherein the volume of anti-CD47 / anti-PD-L1 bispecific antibody-containing liquid pharmaceutical composition administered to the patient is at least 8 ml, and wherein the anti-CD47 I anti-PD-L1 -containing liquid pharmaceutical composition is administered to the patient at a rate of at least 8 ml I hour. Optionally, the anti-CD47 / anti-PD-L1 bispecific antibody is PF-07257876. Optionally, the anti-CD47 / anti-PD- L1 bispecific antibody is administered under these conditions to a patient once every 1 week (QW), once every 2 weeks (Q2W), or once every 3 weeks (Q3W).

In some embodiments, between 1200 mg - 2400 mg of an anti-CD47 / anti-PD- L1 bispecific antibody is administered to a patient via subcutaneous infusion, wherein the anti-CD47 I anti-PD-L1 bispecific antibody is in a liquid pharmaceutical composition that contains between 140 mg/ml - 200 mg/ml anti-CD47 / anti-PD-L1 bispecific antibody, wherein the volume of anti-CD47 / anti-PD-L1 bispecific antibodycontaining liquid pharmaceutical composition administered to the patient is between 8 ml - 24 ml (e.g. 8 ml, 9 ml, 10 ml, 11 ml, 12 ml, 13 ml, 14 ml, 15 ml, 16 ml, 17 ml, 18 ml, 19 ml, 20 ml, 21 ml, 22 ml, 23 ml, or 24 ml), and wherein the anti-CD47 / anti-PD- L1 -containing liquid pharmaceutical composition is administered to the patient at a rate of at between 8 ml / hour - 20 ml / hour (e.g. 8 ml / hour, 9 ml / hour, 10 ml / hour, 11 ml / hour, 12 ml / hour, 13 ml / hour, 14 ml / hour, 15 ml / hour, 16 ml / hour, 17 ml / hour, 18 ml / hour, 19 ml / hour, or 20 ml I hour). Optionally, the anti-CD47 I anti-PD- L1 bispecific antibody is PF-07257876. Optionally, the anti-CD47 I anti-PD-L1 bispecific antibody is administered under these conditions to a patient once every 1 week (QW), once every 2 weeks (Q2W), or once every 3 weeks (Q3W).

In some embodiments, between 1500 mg - 2400 mg of an anti-CD47 / anti-PD- L1 bispecific antibody is administered to a patient via subcutaneous infusion, wherein the anti-CD47 I anti-PD-L1 bispecific antibody is in a liquid pharmaceutical composition that contains between 140 mg/ml - 200 mg/ml anti-CD47 / anti-PD-L1 bispecific antibody, wherein the volume of anti-CD47 / anti-PD-L1 bispecific antibodycontaining liquid pharmaceutical composition administered to the patient is between 8 ml - 24 ml (e.g. 8 ml, 9 ml, 10 ml, 11 ml, 12 ml, 13 ml, 14 ml, 15 ml, 16 ml, 17 ml, 18 ml, 19 ml, 20 ml, 21 ml, 22 ml, 23 ml, or 24 ml), and wherein the anti-CD47 I anti-PD- L1-containing liquid pharmaceutical composition is administered to the patient at a rate of at between 8 ml / hour - 20 ml / hour (e.g. 8 ml / hour, 9 ml / hour, 10 ml / hour, 11 ml / hour, 12 ml / hour, 13 ml / hour, 14 ml / hour, 15 ml / hour, 16 ml / hour, 17 ml / hour, 18 ml / hour, 19 ml / hour, or 20 ml / hour). Optionally, the anti-CD47 / anti-PD- L1 bispecific antibody is PF-07257876. Optionally, the anti-CD47 I anti-PD-L1 bispecific antibody is administered under these conditions to a patient once every 1 week (QW), once every 2 weeks (Q2W), or once every 3 weeks (Q3W).

In some embodiments, between 1800 mg - 2400 mg of an anti-CD47 / anti-PD- L1 bispecific antibody is administered to a patient via subcutaneous infusion, wherein the anti-CD47 I anti-PD-L1 bispecific antibody is in a liquid pharmaceutical composition that contains between 140 mg/ml - 200 mg/ml anti-CD47 / anti-PD-L1 bispecific antibody, wherein the volume of anti-CD47 / anti-PD-L1 bispecific antibodycontaining liquid pharmaceutical composition administered to the patient is between 8 ml - 24 ml (e.g. 8 ml, 9 ml, 10 ml, 11 ml, 12 ml, 13 ml, 14 ml, 15 ml, 16 ml, 17 ml, 18 ml, 19 ml, 20 ml, 21 ml, 22 ml, 23 ml, or 24 ml), and wherein the anti-CD47 / anti-PD- L1-containing liquid pharmaceutical composition is administered to the patient at a rate of at between 8 ml / hour - 20 ml / hour (e.g. 8 ml / hour, 9 ml / hour, 10 ml / hour, 11 ml / hour, 12 ml / hour, 13 ml / hour, 14 ml / hour, 15 ml / hour, 16 ml / hour, 17 ml / hour, 18 ml / hour, 19 ml / hour, or 20 ml / hour). Optionally, the anti-CD47 / anti-PD- L1 bispecific antibody is PF-07257876. Optionally, the anti-CD47 I anti-PD-L1 bispecific antibody is administered under these conditions to a patient once every 1 week (QW), once every 2 weeks (Q2W), or once every 3 weeks (Q3W).

In some embodiments, between 2000 mg - 2400 mg of an anti-CD47 / anti-PD- L1 bispecific antibody is administered to a patient via subcutaneous infusion, wherein the anti-CD47 I anti-PD-L1 bispecific antibody is in a liquid pharmaceutical composition that contains between 140 mg/ml - 200 mg/ml anti-CD47 / anti-PD-L1 bispecific antibody, wherein the volume of anti-CD47 / anti-PD-L1 bispecific antibodycontaining liquid pharmaceutical composition administered to the patient is between 8 ml - 24 ml (e.g. 8 ml, 9 ml, 10 ml, 11 ml, 12 ml, 13 ml, 14 ml, 15 ml, 16 ml, 17 ml, 18 ml, 19 ml, 20 ml, 21 ml, 22 ml, 23 ml, or 24 ml), and wherein the anti-CD47 / anti-PD- L1-containing liquid pharmaceutical composition is administered to the patient at a rate of at between 8 ml / hour - 20 ml / hour (e.g. 8 ml / hour, 9 ml / hour, 10 ml / hour, 11 ml / hour, 12 ml / hour, 13 ml / hour, 14 ml / hour, 15 ml / hour, 16 ml / hour, 17 ml / hour, 18 ml / hour, 19 ml / hour, or 20 ml / hour). Optionally, the anti-CD47 / anti-PD- L1 bispecific antibody is PF-07257876. Optionally, the anti-CD47 I anti-PD-L1 bispecific antibody is administered under these conditions to a patient once every 1 week (QW), once every 2 weeks (Q2W), or once every 3 weeks (Q3W).

The present invention further provides for dosing levels, dosing regimens and methods for the treatment of patients with cancer in which the treatment results in a decrease in a tumor size of at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% as compared to the tumor size in the patient prior to initial administration of the anti-CD47 / anti-PD-L1 bispecific antibody. A decrease in tumor size may be measured or determined by any method used and accepted in the art (e.g., RECIST v.1.1 ).

In some embodiments, a cancer treated with an anti-CD47 / anti-PD-L1 bispecific antibody according to a method provided herein is anti-PD-1 I anti-PD-L1 treatment resistant. An anti-PD-1 I anti-PD-L1 treatment resistant cancer is a cancer that was previously treated with an agent that blocks the interaction between PD-1 and PD-L1 , and for which the cancer has subsequently progressed. In some embodiments, a cancer treated according to a method provided herein is anti-PD-1 I anti-PD-L1 treatment naive. An anti-PD-1 / anti-PD-L1 treatment naive cancer is a cancer that was not previously treated with an agent that blocks the interaction between PD-1 and PD-L1.

Pharmaceutical Compositions

Further provided herein are pharmaceutical compositions comprising an anti- CD47 I anti-PD-L1 bispecific antibody disclosed herein and a pharmaceutically acceptable carrier. The present invention also provides articles of manufacture, comprising a container, a composition within the container comprising an anti-CD47 I anti-PD-L1 bispecific antibody, and a package insert containing instructions to administer a dose of an anti-CD47 I anti-PD-L1 bispecific antibody. Optionally, the anti-CD47 / anti-PD-L1 bispecific antibody is PF-07257876.

Another aspect of the invention provides for kits containing a formulation comprising a pharmaceutical composition. The kits may comprise an anti-CD47 / anti- PD-L1 bispecific antibody and a pharmaceutically acceptable carrier. The kits may contain instructions for Q1W, Q2W, Q3W subcutaneous (injection or infusion) or intravenous dosing of the pharmaceutical composition for the treatment of cancer in which the administration of an anti-CD47 / anti-PD-L1 bispecific antibody is beneficial.

Incorporated by reference herein for all purposes is the content of U.S. Provisional Patent Application No. 63/375,105 filed September 9, 2022.

EXAMPLES

The following examples are meant to illustrate the methods and materials of the present invention. Suitable modifications and adaptations of the described conditions and parameters normally encountered in the art that are obvious to those skilled in the art are within the spirit and scope of the present invention.

Example 1 : Clinical Study of PF-07257876 (anti-CD47 / anti-PD-L1 bispecific) Overall design

This is a Phase 1 , open-label, multi-center, multiple-dose, dose escalation, dose-expansion, safety, PK, and PD study of PF-07257876 as a single agent in cohorts of adult participants with selected advanced or metastatic solid tumors [nonsmall cell lung cancer (NSCLC), squamous cell carcinoma of the head and neck (SCCHN), ovarian cancer (OvCa)], for whom no standard of care therapy is available, and who meet one of the following conditions: (1) participants with NSCLC or SCCHN whose tumors progressed after PD-1/PD-L1 -directed therapy, with or without chemotherapy) or (2) those patients with OvCa whose tumors are refractory to platinum-based therapy.

The study contains 2 parts: Part 1 is single agent dose escalation and Part 2 is a dose expansion at the preliminary recommended Phase 2 dose (RP2D) determined from Part 1. Approximately 90 participants are expected to be enrolled in the study overall with approximately 30 participants enrolled during Part 1 and 20-30 participants enrolled to each of the 2 cohorts during Part 2. The overall study design is depicted in the schema in FIG. 1 .

Participants will receive SC injections of the study treatment Q2W in 28-day cycles. If multiple injections/high volumes of study treatment (e.g., >4 injections or 8 mL) cannot be delivered by SC bolus injections, an alternative method of SC dosing, possibly using a syringe-based infusion pump or other infusion device, will be explored. Alternative dosing schedules (e.g., weekly SC administration) may be considered during the study based on the emerging PK, PD, and safety data.

Part 1 : Dose Escalation

Part 1 will estimate the maximum tolerated dose (MTD) / RP2D in sequential dose-escalation cohorts of PF-07257876 as a single agent in participants with anti- PD-1/L1 relapsed NSCLC and SCCHN. Successive cohorts of 2 to 4 participants per cohort will receive escalating doses of PF-07257876 in 28-day cycles prior to reaching the estimated MTD. At the estimated MTD (or proposed RP2D, if an MTD is not identified), approximately 9 to 15 participants will be treated (including with a limited number of other tumor types, e.g., OvCa). There will be a minimum of 72 hours between the first dose administered to the first participant and administration of PF- 07257876 to the subsequent participants enrolled at the same dose level, to allow for sponsor analysis of initial safety data.

The proposed starting dose will be 150 mg, administered as a flat dose SC Q2W. A Bayesian logistic regression model (BLRM) with escalation with overdose control (EWOC) will be used to guide dose escalation and to determine the MTD. All available data will then be used to identify the preliminary RP2D to be administered in Part 2. To assess baseline biomarkers related to PF-07257876 that may correlate with clinical efficacy, all participants enrolled in Part 1 must fulfill tissue biopsy requirements, which include either (a) submitting a recent archival tumor sample or (b) allowing a fresh pretreatment biopsy during screening, if a recent archival sample is unavailable.

As the MTD/RP2D is being identified in Part 1 , paired de novo pretreatment and on-treatment biopsy samples will be mandatory for the safety expansion cohort to enable evaluation of tissue biomarker PD activity.

Criteria for Dose Escalation:

The purpose of the dose escalation is to identify the maximum tolerated dose (MTD) of the single agent of PF-07257876. The dose escalation will be guided by Bayesian logistic regression model (BLRM) and the escalation with overdose control (EWOC) principle. The use of the EWOC principle limits the risk that a potential next dose will exceed the MTD.

The provisional dose levels to be evaluated are listed in Table 2. Based on emerging tolerability pharmacokinetic (PK) and pharmacodynamic (PD) data, an alternative dose regimen rather than Q2W, i.e., SC Q1W, and dose levels not listed in the table may be evaluated in the escalation phase. The dose increment will not exceed 3-fold at lower dose levels and not exceed 50% when any treatment- emergent adverse events (TEAE) of Grade >2 is observed.

Table 2: Provisional Dose Levels in Dose Escalation

*The dose levels may be adjusted and intermediate doses may be added based on emerging data

**SC infusion pump will be used with cohorts 5-7 Part 2: Dose Expansion

After the appropriate dose for PF-07257876 is selected based on Part 1 data, Part 2 will be initiated in participants with selected solid tumors. Each doseexpansion cohort will enroll approximately 20 to 30 participants with NSCLC and SCCHN (and possibly OvCa, depending upon the findings in Part 1).

Part 2 will evaluate the safety and antitumor activity of the preliminary RP2D selected in Part 1. Participants in Part 2 will receive PF-07257876 at the preliminary RP2D in 28-day cycles. At the end of Part 2, the formal RP2D will be declared, based on the totality of the observed data from this study.

De novo pretreatment biopsies in Part 2 will be required from all participants. Additionally, archival tumor samples are requested to help establish the relationship between target expression, effects of prior therapy, and efficacy observations. If a new biopsy represents a significant safety risk, the participant may be considered for enrollment after discussion of the risk with the sponsor. Discussion with the sponsor will include provision of medical documents that describe the exact risk involved.

Study treatment will continue until progression of disease, participant refusal, unacceptable toxicity, study termination by sponsor, or up to 24 months from the time of the first dose of study treatment of the last participant enrolled in Part 2, whichever occurs first. Participants who complete the maximum number of cycles/months on study treatment and demonstrate clinical benefit with manageable toxicity and are willing to continue receiving the study treatment may be given the opportunity to continue treatment upon agreement between the investigator and sponsor.

Inclusion Criteria

Exemplary inclusion criteria include the following:

Age and Sex:

1. Participants >18 years old at the screening visit.

Type of Participant and Disease Characteristics:

NSCLC and SCCHN

2. Histological or cytological diagnosis of advanced/metastatic NSCLC (regardless of subtype) or SCCHN meeting the following criteria: A) Receipt of exactly 1 prior treatment regimen with a PD-1 or PD-L1 therapy, with or without chemotherapy (in combination or sequentially), in the advanced/metastatic disease setting. B) No prior immunologic therapy may have been given other than anti-PD-1/PD-L1 . C) Prior chemotherapy is not required; participants may have received up to 2 prior chemotherapy regimens.; D) NSCLC Only: Most recent treatment must have included anti-PD-1/PD-L1 therapy.; E) Prior anti-PD-1/PD-L1 therapy must not have been permanently discontinued due to toxicity.

3. Confirmed radiographic progression of disease must have occurred within the following timeframes: A) NSCLC: After at least 12 weeks of therapy, during which time the participant had a best response of either CR, PR, or SD (the SD must be >12 weeks). Note: Participants with “pseudo-progression” within this 12-week time period are eligible to enter the study. Pseudo-progression must be decided upon by the investigator, followed by a discussion with the sponsor. B) SCCHN: After at least 6 weeks of therapy, during which time the participant had a best response of either CR, PR, or SD (SD must be > 6 weeks).

4. NSCLC Only: Confirmed radiographic disease progression must have occurred within <12 weeks after the last dose of the anti-PD-1/PD-L1 therapy.

5. PD-L1 IHC positivity >1%.

6. At least 1 measurable lesion, as defined by RECIST version 1.1 , which has not been irradiated previously.

Ovarian Cancer

7. Histologically confirmed epithelial ovarian, fallopian tube, or peritoneal cancer, including malignant mixed Mullerian tumors with high-grade serous component.

8. Platinum-resistant/refractory disease, defined as disease progression within 6 months following the last administered dose of platinum therapy (resistant), or lack of response or disease progression while receiving the most recent platinum -based therapy (refractory), respectively. 9. May have received up to 3 lines of systemic anticancer therapy for platinumsensitive disease, most recently platinum-containing, and no prior systemic therapy for platinum -resistant or refractory disease. (Note: Receipt of maintenance PARP inhibitor after platinum-containing therapy does not change this criteria).

10. At least 1 measurable lesion, as defined by RECIST version 1.1 , that has not been previously irradiated.

11. Must not have received prior anti-PD-1/PD-L1 therapy.

12. PD-L1 IHC positivity >1%.

Claims

1. A method for the treatment of a patient having cancer, comprising administering to the patient an effective amount of an anti-CD47 I anti-PD-L1 bispecific antibody, wherein the antibody is administered at least twice every week, at least weekly (QW), at least every 2 weeks (Q2W), at least every 3 weeks (Q3W) or at least every 4 weeks (Q4W).

2. The method of claim 1 , wherein the antibody is administered Q2W.

3. The method of any one of claims 1-2, wherein the antibody is administered subcutaneously (SC), intravenously (IV), intramuscularly, by bolus injection, intracerebrally, or by sustained release.

4. The method of any one of claims 1 -3, wherein the antibody is administered at a dose of about 100-3600 mg, about 100-1200 mg, about 450-1200 mg, about 600-1200 mg, about 700-1200 mg, about 800-1200 mg, about 900-1200 mg, about 600-1800 mg, about 600-2400, or about 600-3600 mg.

5. The method of any one of claims 1 -4, wherein the antibody is administered at a dose between a) a lower level of 450, 460, 470, 480, 490, 500, 510, 520, 530, 540,

550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710,

720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880,

890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000, 1010, 1020, 1030, 1040,

1050, 1060, 1070, 1080, 1090, 1100, 1110, 1120, 1130, 1140, 1150, 1160, 1170, 1180, 1190, 1200, 1210, 1220, 1230, 1240, 1250, 1260, 1270, 1280, 1290, or 1300 mg, and b) an upper level of 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000, 1010, 1020, 1030, 1040, 1050, 1060, 1070, 1080, 1090, 1100, 1110, 1120, 1130, 1140, 1150, 1160, 1170, 1180,

1190, 1200, 1210, 1220, 1230, 1240, 1250, 1260, 1270, 1280, 1290, 1300, 1310,

1320, 1330, 1340, 1350, 1360, 1370, 1380, 1390, 1400, 1410, 1420, 1430, 1440,

1450, 1460, 1470, 1480, 1490, 1500, 1510, 1520, 1530, 1540, 1550, 1560, 1570,

1580, 1590, 1600, 1610, 1620, 1630, 1640, 1650, 1660, 1670, 1680, 1690, 1700,

1710, 1720, 1730, 1740, 1750, 1760, 1770, 1780, 1790, 1800, 1810, 1820, 1830,

1840, 1850, 1860, 1870, 1880, 1890, 1900, 1910, 1920, 1930, 1940, 1950, 1960,

1970, 1980, 1990, 2000, 2010, 2020, 2030, 2040, 2050, 2060, 2070, 2080, 2090, 2100, 2110, 2120, 2130, 2140, 2150, 2160, 2170, 2180, 2290, 2300, 2310, 2320, 2330, 2340, 2350, 2360, 2370, 2380, 2390, 2400, 2410, 2420, 2430, 2440, 2450, 2460, 2470, 2480, 2490, or 2500 mg, wherein the lower level is a smaller value than the upper level.

6. The method of any one of claims 1 -5, wherein the antibody is administered SC at a dose of about 150-3600 mg.

7. The method of any one of claims 1-6, wherein the antibody is administered SC at a dose of about 150, 450, 900, 1200, 1800, 2400, or 3600 mg.

8. A method for the treatment of a patient having cancer, comprising administering to the patient an effective amount of an anti-CD47 I anti-PD-L1 bispecific antibody, and wherein the antibody is administered SC at a dose of about 150, 450, 900, 1200, 1800, 2400, or 3600 mg every two weeks (Q2W).

9. The method of any one of claims 1 -8, wherein the antibody is formulated in a pharmaceutical composition.

10. The method of claim 9, wherein the pharmaceutical composition comprises 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, or 200 mg antibody I ml.

11. The method of any one of claims 8-9, wherein the pharmaceutical composition is administered as one or more boluses by SC injection, or as an infusion by SC infusion.

12. The method of claim 11 , wherein 1200 mg or more of the antibody is administered, and the pharmaceutical composition is administered as an infusion by SC infusion.

13. The method of claim 12, wherein the pharmaceutical composition is administered at a rate between 8 ml - 20 ml per hour.

14. The method of any one of claims 12 or 13, wherein between 8 ml - 24 ml of the pharmaceutical composition is administered to the patient.

15. A method for the treatment of a patient having cancer, comprising administering to the patient an effective amount of an anti-CD47 I anti-PD-L1 bispecific antibody, wherein between 1200 mg - 2400 mg of an anti-CD47 / anti-PD-L1 bispecific antibody is administered to a patient via subcutaneous infusion, wherein the anti-CD47 / anti- PD-L1 bispecific antibody is in a liquid pharmaceutical composition that contains between 140 mg/ml - 200 mg/ml anti-CD47 / anti-PD-L1 bispecific antibody, wherein the volume of anti-CD47 / anti-PD-L1 bispecific antibody-containing liquid pharmaceutical composition administered to the patient is between 8 ml - 24 ml, and wherein the anti-CD47 / anti-PD-L1 -containing liquid pharmaceutical composition is administered to the patient at a rate of at between 8 ml / hour - 20 ml / hour.

16. The method of any one of claims 1 -15, wherein the bispecific antibody comprises a first antigen binding portion that binds to CD47 and a second antigen binding portion that binds to PD-L1 , wherein the first antigen binding portion comprises a VH and a VL, wherein the second antigen binding portion comprises a VH and a VL, and wherein: a) the first antigen binding portion VH comprises (i) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 1 , 2, or 3; (ii) a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 4 or 5; and (iii) a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 6; b) the first antigen binding portion VL comprises (i) a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 7; (ii) a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 8; and (iii) a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 9; c) the second antigen binding portion VH comprises (i) a VH CDR1 comprising the amino acid sequence of SEQ ID NO: 14, 15, or 16; (ii) a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 17 or 18; and (iii) a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 19; and d) the second antigen binding portion VL comprises (i) a VL CDR1 comprising the amino acid sequence of SEQ ID NO: 7; (ii) a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 8; and (iii) a VL CDR3 comprising the amino acid sequence of SEQ ID NO: 9.

17. The method of claim 16, wherein the first antigen binding portion VH comprises the amino acid sequence of SEQ ID NO: 10, the first antigen binding portion VL comprises the amino acid sequence of SEQ ID NO: 11 , the second antigen binding portion VH comprises the amino acid sequence of SEQ ID NO: 20, and the second antigen binding portion VL comprises the amino acid sequence of SEQ ID NO: 11.

18. The method of any one of claims 1-17, wherein the antibody comprises an anti- CD47 heavy chain comprising the amino acid sequence of SEQ ID NO: 12 and the antibody comprises an anti-PD-L1 heavy chain comprising the amino acid sequence of SEQ ID NO: 21.

19. The method of claim 18, wherein the antibody further comprises an anti-CD47 light chain comprising the amino acid sequence of SEQ ID NO: 13 and an anti-PD-L1 light chain comprising the amino acid sequence of SEQ ID NO: 13.

20. The method of any one of claims 1 -19, wherein the antibody comprises a first antibody heavy chain, a second antibody heavy chain, a first antibody light chain, and a second antibody light chain; wherein the first antibody heavy chain comprises the amino acid sequence of SEQ ID NO: 12 and the second antibody heavy chain comprises the amino acid sequence of SEQ ID NO: 21 ; and wherein both the first antibody light chain and the second antibody light chain comprise the amino acid sequence of SEQ ID NO: 13.

21. The method of any one of claims 1 -20, wherein the affinity of the anti-PD-L1 antigen binding portion for PD-L1 is greater than the affinity of the anti-CD47 antigen binding portion for CD47.

22. The method of any one of claims 1-21 , wherein the cancer is non-small cell lung cancer (NSCLC), optionally adenocarcinoma NSCLC, squamous cell carcinoma of the head and neck (SCCHN), renal cell carcinoma (RCC), urothelial carcinoma (UC), melanoma, ovarian cancer, or colorectal cancer (CRC).

23. The method of claim 22, wherein a) the CRC is microsatellite stable CRC (MSS CRC), optionally further wherein the MSS CRC is anti-PD-1 I PD-L1 treatment naive, b) the NSCLC, SCCHN, RCC, UC, or melanoma is anti-PD-1 I PD-L1 treatment resistant, or c) the ovarian cancer is anti-PD-1 I PD-L1 treatment naive.

24. The method of any one of claims 1 -23, wherein the treatment results in a decrease in tumor size of at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or 100% as compared to the tumor size in the patient prior to first administration of the bispecific antibody.

25. The method of any one of claims 1 -24, wherein the patient is a human.

26. An anti-CD47 I anti-PD-L1 bispecific antibody for use in treatment of a patient having cancer according to a method as recited in any one of claims 1 -25.

27. Use of an anti-CD47 I anti-PD-L1 bispecific antibody for treatment of cancer according to any one of claims 1 -25.

28. Use of an anti-CD47 I anti-PD-L1 bispecific antibody for the preparation of a medicament for treatment of cancer according to any one of claims 1 -25.