[go: up one dir, main page]

WO2025074328A1 - Utilisation d'anticorps anti-sirp-alpha pour traiter le cancer - Google Patents

Utilisation d'anticorps anti-sirp-alpha pour traiter le cancer Download PDF

Info

Publication number
WO2025074328A1
WO2025074328A1 PCT/IB2024/059746 IB2024059746W WO2025074328A1 WO 2025074328 A1 WO2025074328 A1 WO 2025074328A1 IB 2024059746 W IB2024059746 W IB 2024059746W WO 2025074328 A1 WO2025074328 A1 WO 2025074328A1
Authority
WO
WIPO (PCT)
Prior art keywords
seq
amino acid
acid sequence
variable region
chain variable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/IB2024/059746
Other languages
English (en)
Inventor
Gunther KRETSCHMAR
Kristell MARZIN
Klas PETERSSON
Milena Jozefina TOSIEK
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
OSE Immunotherapeutics SA
Original Assignee
Boehringer Ingelheim International GmbH
OSE Immunotherapeutics SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim International GmbH, OSE Immunotherapeutics SA filed Critical Boehringer Ingelheim International GmbH
Publication of WO2025074328A1 publication Critical patent/WO2025074328A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance

Definitions

  • the present disclosure relates to the treatment of cancer by using an anti-SIRPa (Signal regulatory protein alpha) antibody or antigen-binding fragment thereof.
  • an anti-SIRPa Signal regulatory protein alpha
  • the present disclosure relates to a method of using and uses of an anti-SIRPa antibody or antigen-binding fragment thereof to treat cancer, in a treatment regimen that optionally includes administration of another therapeutic agent.
  • SIRPa is an inhibitory receptor expressed on myeloid cells such as macrophages, neutrophils and subsets of dendritic cells. SIRPa contains three Ig-like domains, a single transmembrane domain, and a cytoplasmic tail with four tyrosine residues which form two typical immunoreceptor tyrosine based inhibitory motifs (ITIMs).
  • the natural ligand for SIRPa is CD47, expressed on many cells including erythrocytes and platelets.
  • SIRPa Binding of SIRPa to CD47 leads to the phosphorylation of the tyrosine residues in SIRPa intracellular ITIM domain and subsequent recruitment and activation SHP-1 and SHP-2 phosphatases at the cell membrane which can then, by dephosphorylation of downstream targets, regulate cellular functions including phagocytosis or antigen presentation.
  • SIRPa In addition to considering polymorphic variants when targeting SIRPa, one also should consider SIRPa’s closest relatives, SIRPpI and SIRPy given their high sequence conservation particularly in N-terminal domains. SIRPpI , like SIRPa is also expressed predominantly on cells of the myeloid lineage, but unlike SIRPa, lacks its own signaling cytoplasmic domain. Instead, it harbors a positively charged amino acid residue within the transmembrane region allowing for the stable association with ITAM-containing adapter molecule DAP12 and therefore is presumed to act as an activating receptor. SIRPpI does not bind CD47, and its ligands have not been identified.
  • SIRPpI isoforms of SIRPpI (Liu et al 2007 J Mol Biol. 2007 Jan 19;365(3):680-93; Brooke et al. 2004 J Immunol. 2004 Aug 15;173(4):2562-70) that arose through tandem duplication of the gene within the SIRP family gene cluster.
  • SIRPy is exclusively expressed on T cells and activated NK cells and does bind to CD47 with 10-fold lower affinity than SIRPa:CD47 interaction. Although it does not have intrinsic signaling capacity, there is reported evidence that it plays a role in T cell trans endothelial migration (TEM) and antigen presentation.
  • TEM T cell trans endothelial migration
  • SIRPa The interaction of SIRPa with CD47 is an important immune checkpoint of the innate response, involved in the regulation of myeloid functions.
  • the interaction between SIRPa and CD47 provides a down-regulatory signal that inhibits host cell phagocytosis. Since CD47 is widely overexpressed in some cancer cells, CD47 functions as a “don’t eat me” signal within tumors comprising these cells, thereby avoiding phagocytosis.
  • anti-human SIRPa antibodies able to disrupt the binding between SIRPa and CD47 have been developed.
  • the disclosure provides a method of treating cancer in a subject in need thereof by administering to the subject a dose of an anti-SIRPa antibody or an antigen-binding fragment thereof.
  • the disclosure provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a dose of about 800 mg to about 3600 mg of an anti-SIRPa antibody or an antigen-binding fragment thereof; wherein the anti-SIRPa antibody or an antigen-binding fragment thereof comprises: a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 33 (H-CDR1); the amino acid sequence of SEQ ID NO: 34 (H-CDR2); and the amino acid sequence of SEQ ID NO: 35 (H-CDR3), and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36 or SEQ ID NO: 37 (L-CDR1); the amino acid sequence of SEQ ID NO: 38 (L-CDR2); and the amino acid sequence of SEQ ID NO: 39 (L-CDR3), or b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 223 (H-
  • the disclosure provides an anti-SIRPa antibody or antigenbinding fragment thereof for use in treating cancer in a subject in need thereof, wherein a dose of about 800 mg to about 3600 mg of the anti-SIRPa antibody or antigen-binding fragment thereof is administered to the subject; wherein the anti-SIRPa antibody or an antigen-binding fragment thereof comprises: a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 33 (H-CDR1); the amino acid sequence of SEQ ID NO: 34 (H- CDR2); and the amino acid sequence of SEQ ID NO: 35 (H-CDR3), and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36 or SEQ ID NO: 37 (L-CDR1); the amino acid sequence of SEQ ID NO: 38 (L-CDR2); and the amino acid sequence of SEQ ID NO: 39 (L-CDR3), or b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:
  • the disclosure provides a use of an anti-SIRPa antibody or antigen-binding fragment thereof in manufacture of a medicament for treating cancer, wherein the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of about 800 mg to about 3600 mg of the anti-SIRPa antibody or antigen-binding fragment thereof; wherein the anti-SIRPa antibody or an antigen-binding fragment thereof comprises: a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 33 (H-CDR1); the amino acid sequence of SEQ ID NO: 34 (H-CDR2); and the amino acid sequence of SEQ ID NO: 35 (H-CDR3), and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36 or SEQ ID NO: 37 (L-CDR1); the amino acid sequence of SEQ ID NO: 38 (L-CDR2); and the amino acid sequence of SEQ ID NO: 39 (L-CDR3), or
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered at a dose of about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered at a dose of about 1400 mg to about 1800 mg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered at a dose of about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered at a dose of about 1400 mg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered at a dose of about 1500 mg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered at a dose of about 1600 mg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered at a dose of about 1700 mg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered at a dose of about 1800 mg.
  • the dose of the anti-SIRPa antibody or the antigen-binding fragment thereof is administered at a dosing cycle of about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), about once every 6 weeks (Q6W), about once every 7 weeks (Q7W), or about once every 8 weeks (Q8W).
  • the dose of the anti-SIRPa antibody or the antigen-binding fragment thereof is administered at a dosing cycle of about once every 2 weeks (Q2W).
  • the dose of the anti-SIRPa antibody or the antigen-binding fragment thereof is administered at a dosing cycle of about once every 3 weeks (Q3W).
  • the method further comprises administering pembrolizumab to the subject.
  • pembrolizumab is administered at a dose of about 400 mg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof and pembrolizumab are administered at a dosing cycle of about once every 3 weeks (Q3W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof and pembrolizumab are administered at a dosing cycle of about once every 6 weeks (Q6W).
  • the method further comprises administering cetuximab to the subject.
  • cetuximab is administered at a dose of about 500 mg/m 2 (e.g., mg of antibody per patient body surface area).
  • cetuximab is administered at a dose of about 500 mg/m 2 .
  • cetuximab is administered at an initial dose of about 400 mg/m2 and a subsequent dose at about 250 mg/m 2 .
  • the anti-SIRPa antibody or the antigen-binding fragment thereof is administered at a dosing cycle of about every 2 weeks (Q2W)
  • pembrolizumab is administered at a dosing cycle of about every 6 weeks (Q6W)
  • cetuximab is administered at a dosing cycle of about every 2 weeks (Q2W).
  • cetuximab is administered at a dosing cycle of about once every 2 weeks (Q2W). In one embodiment, the subsequent dose is administered at a dosing cycle of about once every week (Q1 W).
  • the anti-SIRPa antibody or the antigen-binding fragment thereof comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 33 (H-CDR1); the amino acid sequence of SEQ ID NO: 34 (H-CDR2); and the amino acid sequence of SEQ ID NO: 35 (H-CDR3), and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36 or SEQ ID NO: 37 (L-CDR1); the amino acid sequence of SEQ ID NO: 38 (L-CDR2); and the amino acid sequence of SEQ ID NO: 39 (L-CDR3).
  • the anti-SIRPa antibody or the antigen-binding fragment thereof comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 223 (H-CDR1); the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5 or SEQ ID NO: 224 (H-CDR2); and the amino acid sequence of SEQ ID NO: 6 (H-CDR3); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9 or SEQ ID NO: 225 (L-CDR1); the amino acid sequence of SEQ ID NO: 10, SEQ ID NO: 1 1 or SEQ ID NO: 226 (L-CDR2); and the amino acid sequence of SEQ ID NO: 12 or SEQ ID NO: 227 (L-CDR3).
  • H-CDR1 heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 2
  • the anti-SIRPa antibody or the antigen-binding fragment thereof comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 52 (H-CDR1); the amino acid sequence of SEQ ID NO: 53 (H-CDR2); and the amino acid sequence of SEQ ID NO: 54 (H-CDR3); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 55 (L-CDR1); the amino acid sequence of SEQ ID NO: 56 (L-CDR2); and the amino acid sequence of SEQ ID NO: 57 (L-CDR3).
  • the anti-SIRPa antibody or the antigen-binding fragment thereof comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 33 (H-CDR1); the amino acid sequence of SEQ ID NO: 70 (H-CDR2); and the amino acid sequence of SEQ ID NO: 71 (H-CDR3); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36 (L-CDR1); the amino acid sequence of SEQ ID NO: 72 (L-CDR2); and the amino acid sequence of SEQ ID NO: 39 (L-CDR3).
  • the anti-SIRPa antibody or the antigen-binding fragment thereof comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 243 (H-CDR1); the amino acid sequence of SEQ ID NO: 87 (H-CDR2); and the amino acid sequence of SEQ ID NO: 88 (H-CDR3); and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 36 (L-CDR1); the amino acid sequence of SEQ ID NO: 72 (L-CDR2); and the amino acid sequence of SEQ ID NO: 89 (L-CDR3).
  • the anti-SIRPa antibody or the antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of any one of SEQ ID NOs: 100, 110, 111 , 112, 113, 114, 115, 116, or 117; and a light chain variable region comprising the amino acid sequence of any one of SEQ ID NOs: 105, 125, or 126.
  • the anti-SIRPa antibody or the antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of any one of SEQ ID NOs: 104, 118, 119, 120, 121 , 122, 123, 124 or 221 ; and a light chain variable region comprising the amino acid sequence of any one of SEQ ID NOs: 109, 127, 128, 129, 130, or 222.
  • the anti-SIRPa antibody or the antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of any one of SEQ ID NOs: 100, 101 , 102, 103, or 104; and a light chain variable region comprising the amino acid sequence of any one of SEQ ID NOs: 105, 106, 107, 108, or 109.
  • the anti-SIRPa antibody or the antigen-binding fragment thereof comprises: a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 100; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 105; or b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 110; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 125; or c) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 111 ; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 125; or d) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 112; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 125; or e) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 113; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 113; and
  • the anti-SIRPa antibody or the antigen-binding fragment thereof comprises: a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 104; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 109; or b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 118; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 127; or c) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 118; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 128; or d) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 119; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 127; or e) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 119; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 119; and
  • the anti-SIRPa antibody or the antigen-binding fragment thereof comprises: a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 100; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 105; or b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 101 ; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 106; or c) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 102; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 107; or d) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 103; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 108; or e) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 104; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 104; and
  • the anti-SIRPa antibody or the antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of any one of SEQ ID NO: 131 , 138, 139, 140, 141 , 142, 143, 144, 145, 146, 147, 148, 149, 150, 151 , 152, or 217; and a light chain comprising the amino acid sequence of any one of SEQ ID NO: 174, 181 , 182, 183, 184, 185, 186, 187, 188, 189, 190, 191 , 192, 193, 194, 195, or 218.
  • the anti-SIRPa antibody or the antigen-binding fragment thereof comprises: a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 131 ; and a light chain comprising the amino acid sequence of SEQ ID NO: 174; or b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 138; and a light chain comprising the amino acid sequence of SEQ ID NO: 181 ; or c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 139; and a light chain comprising the amino acid sequence of SEQ ID NO: 182; or d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 140; and a light chain comprising the amino acid sequence of SEQ ID NO: 183; or e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 141 ; and a light chain comprising the amino acid sequence of SEQ ID NO: 184; or f) a heavy chain comprising the amino acid sequence of SEQ ID NO
  • the anti-SIRPa antibody or the antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of any one of SEQ ID NO: 135, 153, 154, 155, 156, 157, 158, 159, 160, 161 , 162, 163, 164, 165, 166, 167, 168, 169, 170, 171 , 172, 173, or 219; and a light chain comprising the amino acid sequence of any one of SEQ ID NO: 178, 196, 197, 198, 199, 200, 201 , 202, 203, 204, 205, 206, 207, 208, 209, 210, 21 1 , 212, 213, 214, 215, 216, or 220.
  • the anti-SIRPa antibody or the antigen-binding fragment thereof comprises: a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 135; and a light chain comprising the amino acid sequence of SEQ ID NO: 178; or b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 153; and a light chain comprising the amino acid sequence of SEQ ID NO: 196; or c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 154; and a light chain comprising the amino acid sequence of SEQ ID NO: 197; or d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 155; and a light chain comprising the amino acid sequence of SEQ ID NO: 198; or e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 156; and a light chain comprising the amino acid sequence of SEQ ID NO: 199; or f) a heavy chain comprising the amino acid sequence
  • the anti-SIRPa antibody or the antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of any one of SEQ ID NO: 131 , 133, 134, 137 or 135; and a light chain comprising the amino acid sequence of any one of SEQ ID NO: 174, 176, 177, 180, or 178.
  • the anti-SIRPa antibody or the antigen-binding fragment thereof comprises: a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 131 ; and a light chain comprising the amino acid sequence of SEQ ID NO: 174; or b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 133; and a light chain comprising the amino acid sequence of SEQ ID NO: 176; or c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 134; and a light chain comprising the amino acid sequence of SEQ ID NO: 177; or d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 137; and a light chain comprising the amino acid sequence of SEQ ID NO: 180; or e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 135; and a light chain comprising the amino acid sequence of SEQ ID NO: 178; or f) a heavy chain comprising the amino acid sequence
  • the subject has been diagnosed with a cancer with solid tumors, in particular advanced solid tumors.
  • the subject has been diagnosed with a SIRPa-positive cancer, a CD47-positive cancer, a PD-1 -positive cancer, or a PD-L1 -positive cancer.
  • the cancer is a cancer with solid tumors expressing or over-expressing SIRPa, CD47, PD-1 and/or PD-L1 .
  • the subject prior to administration of the anti-SIRPa antibody or antigen-binding fragment thereof, has not been treated with an anti-PD-1 antibody or anti-PD-L1 antibody.
  • the subject prior to administration of the anti-SIRPa antibody or antigen-binding fragment thereof, has been treated with an anti-PD-1 antibody or anti-PD-L1 antibody, and has exhibited disease progression.
  • Figures 3A-3C show SIRPa concentration (mg/L) in plasma of human subjects from 0 to 3 weeks post administration of 2000 mg, 2200 mg, 2400 mg, 2600 mg, 2800 mg, 3000 mg, 3200 mg, 3400 mg, or 3600 mg of antibody A10 or 24 mg/kg of antibody X1 (Fig. 3A).
  • Figs. 3B and 3C show the area under the curve (AUC) (mg*h/L) and the median C min (mg/L) at 3 weeks post administration of 2000 mg, 2200 mg, 2400 mg, 2600 mg, 2800 mg, 3000 mg, 3200 mg, 3400 mg, or 3600 mg of antibody A10 or 24 mg/kg of antibody X1 in human subjects.
  • This disclosure relates to anti-SIRPa antibodies or antigen-binding fragments thereof for use in the treatment of conditions modulated by CD47-mediated SIRPa signaling.
  • the disclosure provides methods of treating cancer in a patient comprising administering a therapeutically effective amount of an anti-SIRPa antibody or antigen-binding fragment thereof.
  • the disclosure also provides uses of the anti-SIRPa antibodies or antigenbinding fragments thereof in the treatment of cancer in a patient.
  • This disclosure also relates to the administration of particular doses and dosing cycles which enhance the health of the patient, with the prescribed doses being unexpectedly higher than the typical doses in the field of antibody immunotherapy.
  • These higher doses are well-tolerated without any significant adverse effects both as a monotherapy and as a combination therapy with an additional therapeutic agent such as an anti-PD1 antibody (e.g. pembrolizumab) and/or an anti-epidermal growth factor receptor (EGFR) antibody (e.g, cetuximab).
  • an anti-PD1 antibody e.g. pembrolizumab
  • EGFR anti-epidermal growth factor receptor
  • cetuximab an anti-epidermal growth factor receptor
  • antibodies or immunoglobulin are heterotetrametric glycoproteins, typically of about 150,000 daltons, composed of two identical light (L) chains and two identical heavy (H) chains.
  • Each light chain is covalently linked to a heavy chain by one disulfide bond to form a heterodimer, and the heterotrimeric molecule is formed through a covalent disulfide linkage between the two identical heavy chains of the heterodimers.
  • the light and heavy chains are linked together by one disulfide bond, the number of disulfide linkages between the two heavy chains varies by immunoglobulin isotype.
  • Each heavy and light chain also has regularly spaced intrachain disulfide bridges.
  • VH variable heavy chain
  • CH2 constant domain
  • CH3 constant domain
  • CL carboxyterminal constant domain
  • the VL domain associates non-covalently with the VH domain
  • CL domain is commonly covalently linked to the CH1 domain via a disulfide bond.
  • Particular amino acid residues are believed to form an interface between the light and heavy chain variable domains (Chothia et al., 1985, J. Mol. Biol.
  • variable domains are also referred herein as variable regions, and the constant domains as constant regions.
  • variable domains differ extensively between different antibodies i.e., are “hypervariable.” These hypervariable domains contain residues that are directly involved in the binding and specificity of each particular antibody for its specific antigenic determinant. Hypervariability, both in the light chain and the heavy chain variable domains, is concentrated in three segments known as complementarity determining regions (CDRs) or hypervariable loops (HVLs). CDRs are defined by sequence comparison in Kabat et al., 1991 , In: Sequences of Proteins of Immunological Interest, 5th Ed.
  • HVLs are structurally defined according to the three-dimensional structure of the variable domain, as described by Chothia and Lesk, 1987, J. Mol. Biol. 196: 901-917. Where these two methods result in slightly different identifications of a CDR, the structural definition is preferred.
  • CDR-L1 is positioned at about residues 24-34, CDR-L2, at about residues 50-56, and CDR-L3, at about residues 89-97 in the light chain variable domain;
  • CDR-H1 is positioned at about residues 31 - 35, CDR-H2 at about residues 50-65, and CDR-H3 at about residues 95-102 in the heavy chain variable domain.
  • IMGT and NORTH provide alternative definitions of the CDRs (see, Lefranc MP. Unique database numbering system for immunogenetic analysis. Immunol Today (1997) 18:509; and North B, Lehmann A, Dunbrack RLJ. A new clustering of antibody CDR loop conformations. J Mol Biol.
  • CDRs may be defined per the Chemical Computing Group (CCG) numbering (Almagro et al., Proteins 201 1 ; 79:3050- 3066 and Maier et al, Proteins 2014; 82:1599-1610).
  • CCG Chemical Computing Group
  • the three CDRs within each of the heavy and light chains are separated by framework regions (FR), which contain sequences that tend to be less variable. From the amino terminus to the carboxy terminus of the heavy and light chain variable domains, the FRs and CDRs are arranged in the order: FR1 , CDR1 , FR2, CDR2, FR3, CDR3, and FR4.
  • FR1 , CDR1 , FR2, CDR2, FR3, CDR3, and FR4 The largely p-sheet configuration of the FRs brings the CDRs within each of the chains into close proximity to each other as well as to the CDRs from the other chain. The resulting conformation contributes to the antigen binding site (see Kabat et al., 1991 , NIH Publ. No. 91- 3242, Vol.
  • CDR residues are necessarily directly involved in antigen binding. Those skilled in the art can routinely determine which residues comprise a particular CDR given the variable region amino acid sequence of the antibody.
  • the CDR1 , CDR2, CDR3 of the heavy and light chains therefore define the unique and functional properties specific for a given antibody.
  • FR residues and Ig constant domains are generally not directly involved in antigen binding but contribute to antigen binding and/or mediate antibody effector function. Some FR residues are thought to have a significant effect on antigen binding in at least three ways: by noncovalently binding directly to an epitope, by interacting with one or more CDR residues, and by affecting the interface between the heavy and light chains.
  • the constant domains are not directly involved in antigen binding but mediate various Ig effector functions, such as participation of the antibody in antibody-dependent cellular cytotoxicity (ADCC), complementdependent cytotoxicity (CDC) and antibody-dependent cellular phagocytosis (ADCP).
  • the light chains of vertebrate immunoglobulins are assigned to one of two clearly distinct classes, kappa (K) and lambda (A), based on the amino acid sequence of the constant domain.
  • the heavy chains of mammalian immunoglobulins are assigned to one of five major classes, according to the sequence of the constant domains: IgA, IgD, IgE, IgG, and IgM.
  • IgG and IgA are further divided into subclasses (isotypes), e.g., lgG1 , lgG2, lgG3, lgG4, Ig A1 , and lgA2, respectively.
  • the heavy chain constant domains that correspond to the different classes of immunoglobulins are called an 6, s, y, and p, respectively.
  • the subunit structures and three-dimensional configurations of the classes of native immunoglobulins are well known.
  • antibody and “anti-SIRPa antibody,” are used herein interchangeably and encompass monoclonal antibodies (including full length monoclonal antibodies), multi-specific antibodies (e.g., bispecific antibodies), antibodies with minor modifications such as N- or C-terminal truncations and antibody fragments such as variable domains and other portions of antibodies that exhibit a desired biological activity, e.g., SIRPa binding.
  • the term “monoclonal antibody” refers to an antibody obtained from a substantially homogenous population of antibody molecules, i.e., the individual antibodies comprising the population are identical except for possible well-known alterations such as removal of C-terminal lysine from the antibody heavy chain or post-translational modifications such as amino acid isomerization or deamidation, methionine oxidation or asparagine or glutamine deamidation that may be present.
  • Monoclonal antibodies typically bind one antigenic epitope.
  • a bispecific monoclonal antibody binds two distinct antigenic epitopes.
  • a monoclonal antibody may be monospecific or multi-specific such as bispecific, monovalent, bivalent or multivalent.
  • monoclonal antibodies can be made by any technique or methodology known in the art; including e.g., the hybridoma method (Kohler et al., 1975, Nature 256:495), or recombinant DNA methods known in the art (see, e.g., U.S. Pat. No. 4,816,567), or methods of isolation of monoclonal recombinantly produced using phage antibody libraries, using techniques described in Clackson et al., 1991 , Nature 352: 624-628, and Marks et al., 1991 , J. Mol. Biol. 222: 581-597.
  • Chimeric antibodies consist of the heavy and light chain variable regions of an antibody from one species (e.g., a non-human mammal such as a mouse) and the heavy and light chain constant regions of another species (e.g., human) antibody and can be obtained by linking the DNA sequences encoding the variable regions of the antibody from the first species (e.g., mouse) to the DNA sequences forthe constant regions of the antibody from the second (e.g. human) species and transforming a host with an expression vector containing the linked sequences to allow it to produce a chimeric antibody.
  • a non-human mammal such as a mouse
  • human constant regions of another species
  • the chimeric antibody also could be one in which one or more regions or domains of the heavy and/or light chain is identical with, homologous to, or a variant of the corresponding sequence in a monoclonal antibody from another immunoglobulin class or isotype, or from a consensus or germline sequence.
  • Chimeric antibodies can include fragments of such antibodies, provided that the antibody fragment exhibits the desired biological activity of its parent antibody, for example binding to the same epitope (see, e.g., U.S. Pat. No. 4,816,567; and Morrison et al., 1984, Proc. Natl. Acad. Sci. USA 81 : 6851-6855).
  • antibody fragment refers to a portion of a full length anti-SIRPa antibody, in which a variable region or a functional capability is retained, for example, SIRPa binding.
  • antibody fragments include, but are not limited to, a Fab, Fab', F(ab')2, Fd, Fv, scFv and scFv-Fc fragment, a diabody, a linear antibody, a single-chain antibody, a mini-body, a diabody formed from antibody fragments, and multi-specific antibodies formed from antibody fragments.
  • Antibody fragments can be obtained for example by treating full-length antibodies treated with enzymes such as papain or pepsin to generate useful antibody fragments. Papain digestion is used to produce two identical antigen-binding antibody fragments called “Fab” fragments, each with a single antigen-binding site, and a residual “Fc” fragment. The Fab fragment also contains the constant domain of the light chain and the CH1 domain of the heavy chain. Pepsin treatment yields a F(ab')2 fragment that has two antigen-binding sites and is still capable of cross-linking antigen.
  • enzymes such as papain or pepsin
  • Fab fragments
  • Fab' fragments differ from Fab fragments by the presence of additional residues including one or more cysteines from the antibody hinge region at the C-terminus of the CH1 domain.
  • F(ab')2 antibody fragments are pairs of Fab' fragments linked by cysteine residues in the hinge region. Other chemical couplings of antibody fragments are also known.
  • a “Fv” fragment contains a complete antigen-recognition and binding site consisting of a dimer of one heavy and one light chain variable domain in tight, non-covalent association.
  • the three CDRs of each variable domain interact to define an antigen-biding site on the surface of the VH-VL dimer.
  • the six CDRs confer antigen-binding specificity to the antibody.
  • Antibody fragments may also include “single-chain Fv” or “scFv” fragments.
  • a “single-chain Fv” or “scFv” antibody fragment is a single chain Fv variant comprising the VH and VL domains of an antibody where the domains are present in a single polypeptide chain.
  • the single chain Fv is capable of recognizing and binding antigen.
  • the scFv polypeptide may optionally also contain a polypeptide linker positioned between the VH and VL domains in order to facilitate formation of a desired three-dimensional structure for antigen binding by the scFv (see, e.g., Pluckthun, 1994, in The Pharmacology of Monoclonal Antibodies, Vol. 113, Rosenburg and Moore eds., Springer- Verlag, New York, pp. 269-315).
  • Antibody fragments may also form tandem Fd segments, which comprise a pair of tandem Fd segments (VH-CH1-VH-CH1) to form a pair of antigen binding regions.
  • These “linear antibodies” can be bispecific or monospecific as described in, for example, Zapata et al. 1995, Protein Eng. 8(10): 1057-1062.
  • human antibody as used herein includes antibodies or fragments thereof derived from human germline immunoglobulin sequences.
  • the term “human antibody” is not intended to include antibodies in which CDR sequences derived from the germline of another (mammalian) species, such as a mouse, rat or rabbit, have been grafted onto human framework sequences.
  • the term “human antibody” refers to an antibody or fragment thereof in which every part of the protein (e.g., CDR, framework, CL, CH domains (e.g., CH1 , CH2, CH3), hinge, VL, VH) is substantially non-immunogenic in humans, with only minor sequence changes or variations as further described herein below.
  • a human antibody is distinct from e.g., a chimeric or humanized antibody. It is pointed out that a human antibody can be produced by a non-human animal or prokaryotic or eukaryotic cell that is capable of expressing functionally rearranged human immunoglobulin (e.g., heavy chain and/or light chain) genes.
  • a human antibody can be produced by a non-human animal or prokaryotic or eukaryotic cell that is capable of expressing functionally rearranged human immunoglobulin (e.g., heavy chain and/or light chain) genes.
  • an anti-SIRPa antibody of the disclosure is a humanized antibody or antibody fragment thereof.
  • a humanized antibody or a humanized antibody fragment is a specific type of chimeric antibody which includes an immunoglobulin amino acid sequence variant, or fragment thereof, which is capable of binding to a predetermined antigen and which, comprises one or more FRs having substantially the amino acid sequence of a human immunoglobulin and one or more CDRs having substantially the amino acid sequence of a non-human immunoglobulin.
  • This non-human amino acid sequence often referred to as an “import” sequence is typically taken from an “import” antibody domain, particularly a variable domain.
  • a humanized antibody includes at least the CDRs or HVLs of a non-human antibody, inserted between the FRs of a human heavy or light chain variable domain.
  • Methods of humanization of antibodies are for example described by Almagro et al., (2008) Frontiers in Bioscience 13, 1619-1633, or in WO12092374 A2.
  • the chimeric, humanized or human antibodies or antigen-binding fragments thereof of the present disclosure may further be engineered.
  • Such engineering includes without limitation the removal or exchange of undesired amino acids, for example to reduce immunogenicity in humans, or to avoid deamidation, undesirable charges or lipophilicity or non-specific binding.
  • Such removal or exchange of undesired amino acids can, for example, be introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo.
  • certain mouse FR residues may be retained in an antibody or fragment thereof.
  • an anti-SIRPa antibody comprises substantially all of at least one, and typically two, variable domains (such as contained, for example, in Fab, Fab', F(ab')2, Fabc, and Fv fragments).
  • an anti-SIRPa antibody also includes at least a portion of an immunoglobulin Fc region, typically that of a human immunoglobulin. Ordinarily, the antibody will contain both the light chain as well as at least the variable domain of a heavy chain.
  • the antibody also may include one or more of the CH1 , hinge, CH2, CH3, and/or CH4 regions of the heavy chain, as appropriate.
  • an anti-SIRPa antibody can be selected from any class of immunoglobulins, including IgM, IgG, IgD, IgA and IgE, and any isotype, including lgG1 , lgG2, lgG3, lgG4, Ig A1 and lgA2.
  • An alternative anti-SIRPa antibody can comprise sequences from more than one immunoglobulin class or isotype, and selecting particular modified or unmodified constant domains to optimize desired effector functions is within the ordinary skill in the art.
  • the Fc region of an antibody mediates its serum half-life and effector functions, such as complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cell phagocytosis (ADCP).
  • Fc engineering can be employed to optimize antibody properties suited to the pharmacology activity required of them.
  • cytotoxic activity is not desirable, such as targeting an immune cell in the treatment of cancer
  • the constant domain may be of isotype with reduced effector function, such as lgG4, and/or be modified with known modifications that reduce effector function.
  • the constant domain may be of isotype with increased effector function and/or be modified with known modifications to increase effector function.
  • mutations are known to either reduce or increase effector function. See, e.g., “The future of antibodies as cancer drugs” Janice M Reichert, Eugen Dhimolea, Drug Discov Today (2012) Sep;17(17-18):954-63, “Antibody Drug Discovery” (Volume 4 of Molecular medicine and medicinal chemistry) Clive R. Wood, World Scientific, 2012 ISBN 1848166281 , 9781848166288; “FcyR requirements leading to successful immunotherapy” Immunol Rev. (2015) Nov;268(1):104-22.
  • the constant domain of an antibody of the present disclosure is lgG4Pro, which has one replacement mutation (Ser228Pro) that prevents Fab-arm exchanging.
  • the constant domain of an antibody of the present disclosure is lgG1 , which has two mutations in the constant region, Leu234Ala and Leu235Ala to reduce effector function.
  • the FRs and CDRs, or HVLs, of an engineered anti-SIRPa antibody or antigenbinding fragment thereof need not correspond precisely to the parental sequences.
  • a parental sequence may be altered (e.g., mutagenized) by substitution, insertion or deletion such that the resulting amino acid residue is no longer identical to the original residue in the corresponding position in either parental sequence but the antibody nevertheless retains the function of binding to SIRPa.
  • Such alteration typically will not be extensive and will be conservative alterations.
  • at least 75% of the engineered antibody residues will correspond to those of the parental sequences, more often at least 90%, and most frequently greater than 95%, or greater than 98% or greater than 99%.
  • Immunoglobulin residues that affect the interface between heavy and light chain variable regions (“the VL-VH interface”) are those that affect the proximity or orientation of the two chains with respect to one another. Certain residues that may be involved in interchain interactions include VL residues 34, 36, 38, 44, 46, 87, 89, 91 , 96, and 98 and VH residues 35, 37, 39, 45, 47, 91 , 93, 95, 100, and 103 (utilizing the numbering system set forth in Kabat et al., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md., 1987)). U.S. Pat. No.
  • Consensus sequence and “consensus antibody” refer to an amino acid sequence which comprises the most frequently occurring amino acid residue at each location in all immunoglobulins of any particular class, isotype, or subunit structure, e.g., a human immunoglobulin variable domain.
  • the consensus sequence may be based on immunoglobulins of a particular species or of many species.
  • a “consensus” sequence, structure, or antibody is understood to encompass a consensus human sequence as described in certain embodiments, and to refer to an amino acid sequence which comprises the most frequently occurring amino acid residues at each location in all human immunoglobulins of any particular class, isotype, or subunit structure.
  • the consensus sequence contains an amino acid sequence having at each position an amino acid that is present in one or more known immunoglobulins, but which may not exactly duplicate the entire amino acid sequence of any single immunoglobulin.
  • the variable region consensus sequence is not obtained from any naturally produced antibody or immunoglobulin. Kabat et al., 1991 , Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., and variants thereof.
  • the FRs of heavy and light chain consensus sequences, and variants thereof provide useful sequences for the preparation of human or humanized anti-SIRPa antibodies. See, for example, U.S. Pat. Nos. 6,037,454 and 6,054,297.
  • an “isolated” antibody is one that has been identified and separated and/or recovered from a component of its natural environment or from a cell culture from which it was expressed.
  • An isolated antibody or antibody fragment may have one or more co- or post- translational modifications that arise during production, purification, and/or storage of the antibody or antibody fragment.
  • Contaminant components of the antibody's natural environment are those materials that may interfere with diagnostic or therapeutic uses of the antibody, and can be enzymes, hormones, or other proteinaceous or non-proteinaceous solutes.
  • the antibody will be purified to at least greater than 95% isolation by weight of antibody, for example purified to at least greaterthan 95%, 96%, 97%, 98%, or 99%.
  • An isolated antibody includes an antibody in situ within recombinant cells in which it is produced, since at least one component of the antibody's natural environment will not be present. Ordinarily however, an isolated antibody will be prepared by at least one purification step in which the recombinant cellular material is removed.
  • Multi specific refers to a protein, such as an antibody, that specifically binds two or more distinct antigens or two or more distinct epitopes within the same antigen.
  • Bispecific refers to a protein, such as an antibody, that specifically binds two distinct antigens or two distinct epitopes within the same antigen.
  • the antibody that specifically binds SIRPa or the antigenbinding fragment thereof of the disclosure is a bispecific antibody.
  • the antibody or the antigen-binding fragment thereof of the disclosure is a multi specific antibody.
  • the monospecific antibodies that specifically bind SIRPa provided herein may be engineered into bispecific antibodies, which are also encompassed within the scope of the disclosure.
  • Full-length bispecific antibodies may be generated for example using Fab arm exchange (e.g., half-molecule exchange, exchanging one heavy chain-light chain pair) between two monospecific bivalent antibodies by introducing substitutions at the heavy chain CH3 interface in each half molecule to favor heterodimer formation of two antibody half molecules having distinct specificity either in vitro in cell-free environment or using coexpression.
  • the Fab arm exchange reaction is the result of a disulfide-bond.
  • Bispecific antibodies may also be generated using designs such as the Triomab/Quadroma (Trion Pharma/Fresenius Biotech), Knob-in-Hole (Genentech), CrossMAbs (Roche) and the electrostatically-induced CH3 interaction (Chugai, Amgen, NovoNordisk, Oncomed), the LUZ-Y (Genentech), the Strand Exchange Engineered Domain body (SEEDbody) (EMD Serono), the Biclonic (Merus) and as DuoBody® Products (Genmab A/S).
  • nucleic acids or polypeptide sequences refer to two or more sequences or subsequences that are the same or have a specified percentage of nucleotides or amino acid residues that are the same, when compared and aligned for maximum correspondence.
  • sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first amino acid or nucleic acid sequence for optimal alignment with a second amino or nucleic acid sequence). The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared.
  • a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position.
  • the two sequences that are compared are the same length after gaps are introduced within the sequences, as appropriate (e.g., excluding additional sequence extending beyond the sequences being compared). For example, when variable region sequences are compared, the leader and/or constant domain sequences are not considered.
  • a “corresponding” CDR refers to a CDR in the same location in both sequences (e.g., CDR-H1 of each sequence).
  • the determination of percent identity or percent similarity between two sequences can be accomplished using a mathematical algorithm.
  • a preferred, non-limiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin and Altschul, 1990, Proc. Natl. Acad. Sci. USA 87:2264-2268, modified as in Karlin and Altschul, 1993, Proc. Natl. Acad. Sci. USA 90:5873-5877.
  • Such an algorithm is incorporated into the NBLAST and XBLAST programs of Altschul et al., 1990, J. Mol. Biol. 215:403-410.
  • Gapped BLAST can be utilized as described in Altschul et al., 1997, Nucleic Acids Res. 25:3389-3402.
  • PSI-Blast can be used to perform an iterated search which detects distant relationships between molecules (Id.).
  • BLAST Gapped BLAST
  • PSI-Blast programs the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used.
  • Another preferred, non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, CABIOS (1989). Such an algorithm is incorporated into the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package.
  • ALIGN program version 2.0
  • a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used. Additional algorithms for sequence analysis are known in the art and include ADVANCE and ADAM as described in Torellis and Robotti, 1994, Comput. Appl.
  • a “chemotherapeutic agent” is a chemical compound useful in the treatment of cancer.
  • examples of such chemotherapeutic agents include alkylating agents such a thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylmelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); camptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin, and bizelesin synthetic analogues); cryptophycines (particularly cryptophycin 1
  • dynemicin including dynemicin A; bisphosphonates, such as clodronate; esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromomophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (AdriamycinTM) (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino- doxorubicin, and deoxydoxorubicin), epirubicin, 6-diazo-5-oxo-L-n
  • anti-hormonal agents that act to regulate or inhibit hormone action on tumors
  • SERMs selective estrogen receptor modulators
  • tamoxifen including NolvadexTM
  • raloxifene including NolvadexTM
  • droloxifene 4-hydroxytamoxifen
  • trioxifene keoxifene
  • LY1 17018, onapristone and toremifene (FarestonTM
  • aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, megestrol acetate (MegaceTM), exemestane, formestane, fadrozole, vorozole (RivisorTM), letrozole (FemaraTM), and anastrozole (ArimidexTM
  • anti-androgens such as flutamide, nilutamide, b
  • the antibodies or antigen-binding fragment thereof of the disclosure also may be conjugated to a label, either a label alone or a label and an additional second agent (prodrug, chemotherapeutic agent and the like).
  • a label as distinguished from the other second agents refer to an agent that is a detectable compound or composition and it may be conjugated directly or indirectly to an anti- SIRPa antibody or antigen-binding fragment thereof of the present disclosure.
  • the label may itself be detectable (e.g., radioisotope labels or fluorescent labels) or, in the case of an enzymatic label, may catalyze chemical alteration of a substrate compound or composition that is detectable.
  • Labeled anti-SIRPa antibodies or antigen-binding fragments thereof can be prepared and used in various applications including in vitro and in vivo diagnostics.
  • one or more domains of the anti- SIRPa antibodies orantigen-binding fragments thereof will be recombinantly expressed.
  • Such recombinant expression may employ one or more control sequences, i.e., polynucleotide sequences necessary for expression of an operably linked coding sequence in a particular host organism.
  • the control sequences suitable for use in prokaryotic cells include, for example, promoter, operator, and ribosome binding site sequences.
  • Eukaryotic control sequences include, but are not limited to, promoters, polyadenylation signals, and enhancers. These control sequences can be utilized for expression and production of anti-SIPRa antibodies or antigen-binding fragments thereof in prokaryotic and eukaryotic host cells.
  • a nucleic acid sequence is “operably linked” when it is placed into a functional relationship with another nucleic acid sequence.
  • a nucleic acid presequence or secretory leader is operably linked to a nucleic acid encoding a polypeptide if it is expressed as a preprotein that participates in the secretion of the polypeptide;
  • a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or a ribosome binding site is operably linked to a coding sequence if it is positioned so as to facilitate translation.
  • operably linked means that the DNA sequences being linked are contiguous, and, in the case of a secretory leader, contiguous and in reading frame. However, enhancers are optionally contiguous. Linking can be accomplished by ligation at convenient restriction sites. If such sites do not exist, synthetic oligonucleotide adaptors or linkers can be used.
  • the expressions “cell,” “cell line,” and “cell culture” are used interchangeably and all such designations include the progeny thereof.
  • “transformants” and “transformed cells” include the primary subject cell and cultures derived therefrom without regard for the number of transfers, which may for example have been transfected with one or more expression vectors encoding one or more amino acids sequences of an antibody or antigen-binding fragment thereof of the present disclosure.
  • mammal for purposes of treatment according to the disclosure refers to any animal classified as a mammal, including humans, domesticated and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, and the like.
  • the mammal is a human.
  • a “disorder,” as used herein, is any condition that would benefit from treatment with an anti-SIRPa antibody or antigen-binding fragment thereof described herein. This includes chronic and acute disorders or diseases including those pathological conditions that predispose the mammal to the disorder in question.
  • disorders to be treated herein include inflammatory, angiogenic, autoimmune and immunologic disorders, respiratory disorders, cancer, hematological malignancies, benign and malignant tumors, leukemias and lymphoid malignancies.
  • cancer and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia.
  • SIRPa pathway disorder refers to a condition, which can be alleviated by modulating the interaction between SIRPa and CD47, in particular by inhibiting the SIRPa/CD47 signaling.
  • a “SIRPa pathway disorder” or “SIRPa pathway disease” includes myeloid associated diseases where SIRPa is expressed.
  • a “SIRPa pathway disorder” or “SIRPa pathway disease” also includes conditions characterized by reduced phagocytosis by macrophages and/or dendritic cells that express SIRPa increased immune response is desired.
  • Examples of SIRPa pathway disorders are cancer, inflammatory disease, autoimmune disease, respiratory disease, infectious disease, or fibrosis.
  • cancers include hematological cancer (e.g., leukemia, lymphoma, myeloma, e.g. multiple myeloma), and a metastatic lesion.
  • Further examples include solid tumor cancers.
  • solid tumors include malignancies, e.g. sarcomas and carcinomas, e.g. adenocarcinomas of the various organ systems, such as those affecting the lung, breast, ovarian, lymphoid, gastrointestinal (e.g. colon), anal, genitals and genitourinary tract (e.g.
  • adenocarcinomas which include malignancies such as colon cancers, rectal cancer, renal-cell carcinoma, liver cancer, gastric cancers, non- small cell lung cancer, cancer of the small intestine and cancer of the esophagus.
  • the cancer may be at an early, intermediate, late stage or metastatic cancer.
  • the cancer is chosen from a lung cancer (e.g. NSCLC (e.g. a NSCLC with squamous and/or non-squamous histology, or a NSCLC adenocarcinoma)), a melanoma (e.g. an advanced melanoma), a renal cancer (e.g. a renal cell carcinoma), a liver cancer, hepatocellular carcinoma, a myeloma (e.g. a multiple myeloma), a prostate cancer, a breast cancer (e.g. a breast cancerthat does not express one, two or all of estrogen receptor, progesterone receptor, or HER2/neu, e.g.
  • a lung cancer e.g. NSCLC (e.g. a NSCLC with squamous and/or non-squamous histology, or a NSCLC adenocarcinoma)
  • a melanoma e.g. an advanced
  • a triple negative breast cancer a colorectal cancer, a pancreatic cancer, a head and neck cancer (e.g. head and neck squamous cell carcinoma (HNSCC), anal cancer, gastro-esophageal cancer, thyroid cancer, cervical cancer, a lymphoproliferative disease (e.g. a post-transplant lymphoproliferative disease) or a hematological cancer, T cell lymphoma, B-cell lymphoma, a non-Hodgkin lymphoma, or a leukemia (e.g. a myeloid leukemia or a lymphoid leukemia).
  • HNSCC head and neck squamous cell carcinoma
  • a lymphoproliferative disease e.g. a post-transplant lymphoproliferative disease
  • a hematological cancer T cell lymphoma, B-cell lymphoma, a non-Hodgkin lymphoma, or a leukemia (e.g.
  • the cancer is chosen from a carcinoma (e.g. advanced or metastatic carcinoma), melanoma or a lung carcinoma, e.g. a NSCLC.
  • a carcinoma e.g. advanced or metastatic carcinoma
  • melanoma e.g. a melanoma
  • a lung carcinoma e.g. a NSCLC.
  • the cancer is chosen from a pancreatic cancer, prostate cancer, breast cancer, colorectal cancer, lung cancer, glioblastoma, renal cancer, preferably pancreatic cancer, prostate cancer, breast cancer, colorectal cancer or lung cancer.
  • the cancer is pancreatic cancer, lung cancer, breast cancer, melanoma, colorectal cancer, ovarian cancer, gastric cancer, thyroid cancer, liver cancer or prostate cancer.
  • binding agent e.g., an antibody or antigen-binding fragment thereof
  • a binding agent that associates more frequently, more rapidly, with greater duration, with greater affinity, with greater avidity or with some combination of the above, to an antigen or an epitope within the antigen than with an unrelated antigen.
  • an antibody or antigenbinding fragment thereof specifically binds to an antigen or epitope within an antigen with a KD of about 0.1 mM or less, preferably less than about 1 pM.
  • specific binding can include an antibody or antigen-binding fragment thereof that recognizes a protein in more than one species (e.g., human SIRPa and cyno SIRPa). It is understood that, in certain embodiments, an antibody or antigen-binding fragment thereof that specifically binds a first protein may or may not specifically bind a second protein. As such, “specific binding” does not necessarily require (although it can include) exclusive binding, i.e. binding to a single protein. Thus, an antibody or antigen-binding fragment thereof may, in certain embodiments, specifically bind more than one protein.
  • Methods for determining whether two molecules specifically bind a protein include, for example, equilibrium dialysis, surface plasmon resonance, and the like.
  • specific binding is characterized by a KD of about 1 x 10.-7 M (100 nM) or less, about 5 x 10.-8 M (50 nM) or less, about 1 x 10.-8 M (10 nM) or less, or about 5 x 10.-9 M (5 nM) or less according.
  • subcutaneous administration refers to introduction of a drug, for example an anti-SIRPa antibody or antigen-binding fragment thereof of the disclosure, under the skin of a subject such as an animal or human patient, preferable within a pocket between the skin and underlying tissue, by relatively slow, sustained delivery from a drug receptacle. Pinching or drawing the skin up and away from underlying tissue may create the pocket.
  • a drug for example an anti-SIRPa antibody or antigen-binding fragment thereof of the disclosure
  • subcutaneous infusion refers to introduction of a drug, for example an anti-SIRPa antibody or antigen-binding fragment thereof of the disclosure, under the skin of a subject, preferably within a pocket between the skin and underlying tissue, by relatively slow, sustained delivery from a drug receptacle for a period of time including, but not limited to, 30 minutes or less, or 90 minutes or less.
  • the infusion may be made by subcutaneous implantation of a drug delivery pump implanted under the skin of the subject, wherein the pump delivers a predetermined amount of drug for a predetermined period of time, such as 30 minutes, 90 minutes, or a time period spanning the length of the treatment regimen.
  • subcutaneous bolus refers to drug administration beneath the skin of a subject, where bolus drug delivery is less than approximately 15 minutes; in another aspect, less than 5 minutes, and in still another aspect, less than 60 seconds. In yet even another aspect, administration is within a pocket between the skin and underlying tissue, where the pocket may be created by pinching or drawing the skin up and away from underlying tissue.
  • subcutaneous bolus refers to the administration of an anti-SIRPa antibody or antigen-binding fragment thereof of the disclosure to a subject in less than approximately 15 minutes; in another aspect, less than 5 minutes, and in still another aspect, less than 60 seconds.
  • the term “therapeutically effective amount” is used to refer to an amount of an anti-SIRPa antibody or antigen-binding fragment thereof that relieves or ameliorates one or more of the symptoms of the disorder being treated. In doing so, it is that amount that has a beneficial patient outcome. Efficacy can be measured in conventional ways, depending on the condition to be treated. [00110]
  • treatment and “therapy” and the like, as used herein, are meant to include therapeutic as well as prophylactic, orsuppressive measures for a disease ordisorder leading to any clinically desirable or beneficial effect, including but not limited to alleviation or reliefofone ormore symptoms, regression, slowing orcessation of progression ofthe disease ordisorder.
  • the term treatment includes the administration of an anti-SIRPa antibody or antigen-binding fragment thereof prior to or following the onset of a symptom of a disease or disorder thereby preventing or removing one or more signs of the disease or disorder.
  • the term includes the administration of an anti-SIRPa antibody or antigen-binding fragment thereof after clinical manifestation of the disease to combat the symptoms ofthe disease.
  • administration of an anti-SIRPa antibody or antigen-binding fragmentthereof after onset and after clinical symptoms have developed where administration affects clinical parameters of the disease or disorder, such as the degree of tissue injury or the amount or extent of metastasis, whether or not the treatment leads to amelioration of the disease, comprises “treatment” or “therapy” as used herein.
  • compositions of the disclosure either alone or in combination with another therapeutic agent alleviate or ameliorate at least one symptom of a disorder being treated as compared to that symptom in the absence of use of the anti-SIRPa antibody or antigen-binding fragment thereof, the result should be considered an effective treatment of the underlying disorder regardless of whether all the symptoms of the disorder are alleviated or not.
  • package insert is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, administration, contraindications and/or warnings concerning the use of such therapeutic products.
  • anti-SIRPa antibodies and antigen-binding fragments thereof for use in the treatment of a variety of diseases or disorders, in particular diseases or disorders characterized by modulation of CD47-mediated SIRPa signaling.
  • the anti-SIRPa antibody or antigen-binding fragment thereof blocks the interaction between SIRPa and CD47, in particular, between human SIRPa and human CD47.
  • the anti-SIRPa antibody orantigen-binding fragmentthereof does not block the interaction between SIRPy and CD47.
  • An antibody or an antigen-binding fragment thereof may be considered to block the interaction between SIRPa and CD47 when the antibody, or the antigen-binding fragment thereof, has an antagonist effect on the CD47/SIRPa interaction.
  • the decrease or the inhibition of the binding of CD47 to SIRPa, in particular human CD47 to human SIRPa means that the antibody or antigen-binding fragment thereof decreases the interaction between SIRPa and CD47, i.e., the antibody or antigen-binding fragment thereof partially or fully inhibits the binding of SIRPa to CD47 or in other words, antagonizes the interaction between SIRPa and CD47.
  • the anti-SIRPa antibody or antigenbinding fragment thereof has the capability to decrease or inhibit the binding of CD47 to SIRPa, in particular the binding of human CD47 to human SIRPa, by at least 50%, such as at least 60%, at least 70%, at least 80%, at least 90%, or by 100%, as compared to a negative control molecule in a binding assay.
  • the anti-SIRPa antibody or antigen-binding fragment thereof has the capability to decrease or inhibit the binding of CD47 to SIRPa, in particularthe binding of human CD47 to human SIRPa, from 50% to 100%, such as from 50% to 90%, 60 % to 90%, or70% to 80%, as compared to a negative control molecule in a binding assay.
  • the anti-SIRPa antibodies and antigen-binding fragments thereof disclosed herein recognizes a specific linear and/or conformational SIRPa antigen epitope and SIRPa epitope.
  • Suitable SIRPa antigen epitopes and SIRPa epitopes include, but are not limited to, those disclosed in WO 2022/254379, which is hereby incorporated by reference in its entirety.
  • CDRs of representative anti-SIRPa antibodies of the present disclosure are provided in Tables 1-25 below.
  • Heavy Chain CDR-1 , CDR-2, CDR3 (HCDR1-3) and Light Chain CDR-1 , CDR-2, CDR3 (L-CDR1 -3) are provided according to the numbering systems according to Kabat, CCG, Chothia, IMGT, and North.
  • Representative anti-SIRPa antibodies of the present disclosure have the light and/or heavy chain variable regions sequences as set forth in Tables 28 or 29.
  • Representative anti-SIRPa antibodies of the present disclosure may comprise a heavy and/or light chain as set forth in Tables 30 or 31 below.
  • Representative anti-SIRPa antibodies of the present disclosure may comprise a heavy and/or light chain constant region as set forth in Tables 32 or 33 below.
  • Variant anti-SIRPa antibodies and antibody fragments thereof can be engineered based on a set of CDRs depicted in Tables 1-25. It is to be understood that in the variant anti- SIRPa antibodies and antibody fragments the amino acid sequence of the CDRs remain unchanged or have minimal changes (e.g., 1-5 changes), but the surrounding regions, e.g., FR regions can be engineered. Amino acid sequence variants of the anti-SIRPa antibody can be prepared by introducing appropriate nucleotide changes into the anti-SIRPa antibody DNA, or by peptide synthesis.
  • Such variants include, for example, deletions from, and/or insertions into and/or substitutions of, residues within the amino acid sequences of the anti-SIRPa antibodies of the examples herein. Any combination of deletions, insertions, and substitutions is made to arrive at the final construct, provided that the final construct possesses the desired characteristics.
  • the amino acid changes also may alter post-translational processes of the human or variant anti-SIRPa antibody, such as changing the number or position of glycosylation sites.
  • the present disclosure includes anti-SIRPa antibodies or antibody fragments thereof having a variable heavy chain and a variable light chain, wherein the variable heavy chain amino acid sequence and the variable light chain amino acid sequence are at least at least 90%, at least 92.5%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequences disclosed in Tables 26-29 provided that the antibody or fragments thereof retain binding to SIRPa-V1 and/or SIRPa-V2.
  • the present disclosure includes anti-SIRPa antibodies or antibody fragments thereof having a variable heavy chain and a variable light chain, wherein the variable heavy chain amino acid sequence and the variable light chain amino acid sequence are at least 80%, at least 85%, at least 90%, at least 92.5%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequences of SEQ ID Nos: 100, 101 , 102, 103, 110, 111 , 112, 113, 114, 115, 116, 117, 104, 118, 119, 120, 121 , 122, 123, 124, or 221 , and SEQ ID Nos: 105, 106, 107, 108,109, 126, 127, 128, 129, 130, or 222, respectively.
  • the present disclosure includes anti-SIRPa antibodies having a heavy chain and a light chain, wherein the heavy chain amino acid sequence and the light chain amino acid sequence are at least 95%, at least 98%, or at least 99% identical to the amino acid sequences disclosed in Tables 30 and 31 provided that the antibody or fragments thereof retain binding to SIRPa-V1 and/or SIRPa-V2.
  • the anti-SIRPa antibodies or antibody fragments thereof comprise a variable heavy chain sequence that comprises an amino acid sequence with at least about 95%, about 96%, about 97%, about 98%, or about 99%, sequence identity to the amino acid sequence set forth in SEQ ID NOs: 100, 101 , 102, 103, 110, 111 , 112, 113, 114, 115, 116, 117, 104, 118, 119, 120, 121 , 122, 123, 124, or221.
  • the anti- SIRPa antibodies or antibody fragments thereof retains the binding and/or functional activity of an anti-SIRPa antibody or antibody fragment thereof that comprises the variable heavy chain sequence of SEQ ID NOs: 100, 101 , 102, 103, 110, 111 , 112, 113, 114, 115, 116, 117, 104, 118, 119, 120, 121 , 122, 123, 124, or 221 .
  • the anti-SIRPa antibodies or antibody fragments thereof comprise the variable heavy chain sequence of SEQ ID NOs: 100, 101 , 102, 103, 110, 111 , 112, 113, 114, 115, 116, 117, 104, 118, 119, 120, 121 , 122, 123, 124, or 221 and have one or more conservative amino acid substitutions, e.g., 1 , 2, 3, 4, 5, 1-2, 1-3, 1-4 or 1-5 conservative amino acid substitutions in the heavy chain variable sequence.
  • the one or more conservative amino acid substitutions fall within one or more framework regions in SEQ ID NOs: 100, 101 , 102, 103, 110, 111 , 112, 113, 114, 115, 116, 117, 104, 118, 119, 120, 121 , 122, 123, 124, or 221 (based on the numbering system of Kabat).
  • the anti-SIRPa antibody or antibody fragment thereof comprises a variable heavy chain sequence with at least about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to the anti-SIRPa heavy chain variable region sequence set forth in 100, 101 , 102, 103, 110, 111 , 112, 113, 114, 115, 116, 117, 104, 118, 119, 120, 121 , 122, 123, 124, or 221 comprises one or more conservative amino acid substitutions in a framework region (based on the numbering system of Kabat), and retains the binding and/or functional activity of an anti-SIRPa antibody or antibody fragment thereof that comprises a variable heavy chain sequence as set forth in SEQ ID NOs: 100, 101 , 102, 103, 110, 111 , 112, 113, 114, 115, 116, 117, 104, 118, 119, 120, 121 , 122, 123, 124, or
  • the anti-SIRPa antibodies or antibody fragments thereof comprise a variable light chain sequence that comprises an amino acid sequence with at least about 95%, about 96%, about 97%, about 98%, or about 99%, sequence identity to the amino acid sequence set forth in SEQ ID NOs: 105, 106, 107, 108,109, 126,127, 128, 129, 130, or 222.
  • the anti-SIRPa antibodies or antibody fragments thereof retains the binding and/or functional activity of an anti-SIRPa antibody or antibody fragment thereof that comprises the variable light chain sequence of SEQ ID NOs: 105, 106, 107, 108,109, 126, 127, 128, 129, 130, or 222.
  • the anti-SIRPa antibodies or antibody fragments thereof comprise the variable light chain sequence of SEQ ID NOs: 105, 106, 107, 108,109, 126, 127, 128, 129, 130, or 222 and have one or more conservative amino acid substitutions, e.g., 1 , 2, 3, 4, 5, 1-2, 1-3, 1-4 or 1-5 conservative amino acid substitutions in the light chain variable sequence.
  • the one or more conservative amino acid substitutions fall within one or more framework regions in SEQ ID NOs: 105, 106, 107, 108,109, 127, 128, 129, 130, or 222 (based on the numbering system of Kabat).
  • the anti-SIRPa antibody or antibody fragment thereof comprises a variable light chain sequence with at least about 95%, about 96%, about 97%, about 98%, or about 99% sequence identity to the anti-SIRPa light chain variable region sequence set forth in SEQ ID NOs: 105, 106, 107, 108,109, 126, 127, 128, 129, 130, or 222 comprises one or more conservative amino acid substitutions in a framework region (based on the numbering system of Kabat), and retains the binding and/or functional activity of an anti-SIRPa antibody or antibody fragment thereof that comprises a variable heavy chain sequence as set forth in SEQ ID NOs: 100, 101 , 102, 103, 110, 111 , 112, 113, 114, 115, 116, 117, 104, 118, 119, 120, 121 , 122, 123, 124, or 221 and a variable light chain sequence as set forth in SEQ ID NOs: 105, 106,
  • the present disclosure includes anti-SIRPa antibodies or antigen-binding fragments thereof having an amino acid substitution. These variants have at least one amino acid residue in the anti-SIRPa antibody or antigen-binding fragment thereof removed and a different residue inserted in its place.
  • the sites of greatest interest for substitutional mutagenesis include the hypervariable regions, but FR alterations are also contemplated. Conservative substitutions are shown in Table 33 under the heading of “preferred substitutions.” If such substitutions result in a change in biological activity, then more substantial changes, denominated “exemplary substitutions,” or as further described below in reference to amino acid classes, may be introduced and the products screened.
  • the biological properties of the antibody can be accomplished by selecting substitutions that differ significantly in their effect on maintaining (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain.
  • Naturally occurring residues are divided into groups based on common side-chain properties:
  • hydrophobic norleucine, met, ala, val, leu, ile
  • Non-conservative substitutions will entail exchanging a member of one of these classes for another class.
  • cysteine residue not involved in maintaining the proper conformation of the anti-SIRPa antibody or antigen-binding fragment thereof also may be substituted, generally with serine, to improve the oxidative stability of the molecule, prevent aberrant crosslinking, or provide for established points of conjugation to a cytotoxic or cytostatic compound.
  • cysteine bond(s) may be added to the antibody or antigen-binding fragment thereof to improve its stability (particularly where the antibody is an antibody fragment such as an Fv fragment).
  • Another type of amino acid variant of the antibody involves altering the original glycosylation pattern of the antibody.
  • altering in this context means deleting one or more carbohydrate moieties found in the antibody, and/or adding one or more glycosylation sites that were not previously present in the antibody.
  • an antibody may comprise an amino acid substitution at position 297 of the human lgG1 heavy chain to abrogate oligosaccharyltransferase enzyme complex-mediated glycosylation by replacing the asparagine 297 (e.g. N297A, N297G).
  • Nucleic acid molecules encoding amino acid sequence variants of an anti-SIRPa antibody or antigen-binding fragment thereof are prepared by a variety of methods known in the art. These methods include, but are not limited to, isolation from a natural source (in the case of naturally occurring amino acid sequence variants) or preparation by oligonucleotide- mediated (or site-directed) mutagenesis, PCR mutagenesis, and cassette mutagenesis of an earlier prepared variant or a non-variant version of the anti-SIRPa antibody or antigen-binding fragment thereof.
  • the anti-SIRPa antibody is an antibody fragment.
  • Fragments can be derived via proteolytic digestion of intact antibodies (see, e.g., Morimoto et al., 1992, Journal of Biochemical and Biophysical Methods 24:107-117; and Brennan et al., 1985, Science 229:81).
  • the fragments can be produced directly in recombinant host cells.
  • Fab'-SH fragments can be directly recovered from E. coli and chemically coupled to form F(ab')2 fragments (see, e.g., Carteret al., 1992, Bio/Technology 10:163-167).
  • F(ab')2 fragments can be isolated directly from recombinant host cell culture.
  • Other techniques for the production of antibody fragments will be apparent to a skilled practitioner.
  • the anti-SIRPa antibodies and antigen-binding fragments thereof can include modifications, such as glycosylation, oxidation, or deamidation.
  • an anti-SIRPa antibody fragment rather than an intact antibody. It may be desirable to modify the antibody fragment in order to increase its serum half-life. This can be achieved, for example, by incorporation of a salvage receptor binding epitope into the antibody fragment.
  • the appropriate region of the antibody fragment can be altered (e.g., mutated), or the epitope can be incorporated into a peptide tag that is then fused to the antibody fragment at either end or in the middle, for example, by DNA or peptide synthesis (see, e.g., WO 96/32478).
  • antibody fragments of the disclosure may also be fused to human serum albumin to increase the serum half-life, if the use of a full-length IgG scaffold is undesirable.
  • Such fusion proteins of the antibody fragment with human serum albumin may be advantageous in situations in which two different antibody fragments need to be fused to increase avidity, or to generate a bispecific binding protein with extended serum half-life (see e.g. WO 05/077042 A2).
  • Another type of useful modification comprises linking the antibody to one of a variety of nonproteinaceous polymers, e.g., polyethylene glycol, polypropylene glycol, or polyoxyalkylenes, in the manner set forth in one or more of U.S. Pat. No. 4,640,835, U.S. Pat. No. 4,496,689, U.S. Pat. No. 4,301 ,144, U.S. Pat. No. 4,670,417, U.S. Pat. No. 4,791 ,192 and U.S. Pat. No. 4,179,337.
  • nonproteinaceous polymers e.g., polyethylene glycol, polypropylene glycol, or polyoxyalkylenes
  • the anti-SIRPa antibody or antigen-binding fragment thereof may be administered to a subject at a dose of about 800 mg to about 3600 mg (e.g., about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg), about 1600 mg to about 3600 mg, about 2400 mg to about 3600 mg, or about 1600 mg to about 2400 mg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to the subject.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1400 mg to about 1800 mg (e.g., about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1400 mg to about 1500 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1500 mg to about 1600 mg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1600 mg to about 1700 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1700 mg to about 1800 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of at least 800 mg to at least 3600 mg (e.g., at least 800 mg, at least 900 mg, at least 1000 mg, at least 1100 mg, at least 1200 mg, at least 1300 mg, at least 1400 mg, at least 1500 mg, at least 1600 mg, at least 1700 mg, at least
  • 1800 mg at least 1900 mg, at least 2000 mg, at least 2100 mg, at least 2200 mg, at least
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of at least 1400 mg to at least 1800 mg (e.g., at least 1400 mg, at least 1500 mg, at least 1600 mg, at least 1700 mg, or at least 1800 mg). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of at least 1400 mg to at least 1500 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of at least 1500 mg to at least 1600 mg.
  • the anti- SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of at least 1600 mg to at least 1700 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of at least 1700 mg to at least 1800 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of at least 1400 mg, at least 1500 mg, at least 1600 mg, at least 1700 mg, or at least 1800 mg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of about 800 mg to about 3600 mg (e.g., about 800 mg, about 900 mg, about 1000 mg, about 1 100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg), about 1600 mg to about 3600 mg, about 2400 mg to about 3600 mg, or about 1600 mg to about 2400 mg.
  • about 800 mg to about 3600 mg e.g., about 800 mg, about 900 mg, about 1000 mg, about 1 100 mg, about 1200 mg, about 1300 mg, about 1
  • the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of about 1400 mg to about 1800 mg (e.g., about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of about 1400 mg to about 1500 mg. In some embodiments, the anti- SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of about 1500 mg to about 1600 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of about 1600 mg to about 1700 mg.
  • the anti-SIRPa antibody orantigen-binding fragment thereof is formulated for administration at a dose of about 1700 mg to about 1800 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of at least 800 mg to at least 3600 mg (e.g., at least 800 mg, at least 900 mg, at least 1000 mg, at least 1 100 mg, at least 1200 mg, at least 1300 mg, at least 1400 mg, at least 1500 mg, at least 1600 mg, at least 1700 mg, at least 1800 mg, at least 1900 mg, at least 2000 mg, at least 2100 mg, at least 2200 mg, at least 2300 mg, at least 2400 mg, at least 2500 mg, at least 2600 mg, at least 2700 mg, at least 2800 mg, at least 2900 mg, at least 3000 mg, at least 3100 mg, at least 3200 mg, at least 3300 mg, at least 3400 mg, at least 3500 mg, or at least 3600 mg).
  • at least 800 mg to at least 3600 mg e.g., at least 800 mg, at least 900 mg, at least 1000 mg, at least 1 100 mg, at least 1200
  • the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of at least 1400 mg to at least 1800 mg (e.g., at least 1400 mg, at least 1500 mg, at least 1600 mg, at least 1700 mg, or at least 1800 mg). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of at least 1400 mg to at least 1500 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of at least 1500 mg to at least 1600 mg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of at least 1600 mg to at least 1700 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of at least 1700 mg to at least 1800 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is formulated for administration at a dose of at least 1400 mg, at least 1500 mg, at least 1600 mg, at least 1700 mg, or at least 1800 mg. [00145] In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered more than one time to the subject.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered in a dosing cycle, wherein the dosing cycle is the time period between one administration of the anti-SIRPa antibody or antigen-binding fragment thereof and the next administration of the anti-SIRPa antibody or antigen-binding fragment thereof, for example, between the first administration of the anti- SIRPa antibody or antigen-binding fragment thereof and the second administration of the anti- SIRPa antibody or antigen-binding fragment thereof.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered several times according to a regular dosing cycle, e.g., the time period between each administration is the same, such as every two weeks (Q2W).
  • dosing cycles are interrupted by a treatment- free period of time. In other embodiments, dosing cycles are not interrupted by a treatment- free period of time.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered at a dosing cycle (administration interval) of about once every 2 weeks (Q2W) to about once every 8 weeks (Q8W) (e.g., about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), about once every 6 weeks (Q6W), about once every 7 weeks (Q7W), or about once every 8 weeks (Q8W)).
  • a dosing cycle administration interval of about once every 2 weeks (Q2W) to about once every 8 weeks (Q8W) (e.g., about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), about once every 6 weeks (Q6W), about once every 7 weeks (Q7W), or about once every 8 weeks (Q8W)).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered at a dosing cycle of about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), about once every 6 weeks (Q6W), about once every 7 weeks (Q7W), or about once every 8 weeks (Q8W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered at a dosing cycle (administration interval) of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered at a dosing cycle (administration interval) of about once every 3 weeks (Q3W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 800 mg to about 3600 mg (e.g., about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg), about 1600 mg to about 3600 mg, about 2400 mg to about 3600 mg, or about 1600 mg to about 2400 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W) to about once every 8 weeks (Q8W) (e.g.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 800 mg, about 900 mg, about 1000 mg, about 1 100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), about once every 6 weeks (Q6W), about once every 7 weeks (Q7W), or about once every 8 weeks (Q8W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 800 mg to about 3600 mg (e.g., about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg), about 1600 mg to about 3600 mg, about 2400 mg to about 3600 mg, or about 1600 mg to about 2400 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W).
  • a dosing cycle administration interval
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 800 mg, about 900 mg, about 1000 mg, about 1 100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W).
  • a dosing cycle administration interval
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1400 mg to about 1800 mg (e.g., about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg) at a dosing cycle (administration interval) of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1400 mg to about 1500 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1500 mg to about 1600 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1600 mg to about 1700 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1700 mg to about 1800 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1400 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1500 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1600 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1700 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1800 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1400 mg to about 3600 mg (e.g., 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg) at a dosing cycle (administration interval) of about once every 3 weeks (Q3W).
  • a dosing cycle administration interval
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W).
  • a dosing cycle administration interval
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1400 mg to about 1800 mg (e.g., about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg) at a dosing cycle (administration interval) of about once every 3 weeks (Q3W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1400 mg to about 1500 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1500 mg to about 1600 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1600 mg to about 1700 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W). In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1700 mg to about 1800 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1400 mg at a dosing cycle (administration interval) of at least once every 3 weeks (Q3W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1500 mg at a dosing cycle (administration interval) of at least once every 3 weeks (Q3W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1600 mg at a dosing cycle (administration interval) of at least once every 3 weeks (Q3W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1700 mg at a dosing cycle (administration interval) of at least once every 3 weeks (Q3W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1800 mg at a dosing cycle (administration interval) of at least once every 3 weeks (Q3W).
  • the anti-SIRPa antibodies or antigen-binding fragments thereof of the disclosure are useful fortreating and/or preventing SIRPa pathway disorders.
  • the anti-SIRPa antibodies or antigen-binding fragments thereof of the disclosure are useful as a medicament.
  • the disclosure provides a method of modulating the interaction between SIRPa and CD47 in a patient comprising administering to the patient an anti-SIRPa antibody or antigen-binding fragment thereof in an amount sufficient to block CD47-mediated SIRPa signaling in the patient.
  • the disclosure provides an anti-SIRPa antibody or antigen-binding fragment thereof for use in modulating the interaction between SIRPa and CD47 in a subject.
  • the disclosure provides the use of an anti-SIRPa antibody or antigen-binding fragment thereof in the manufacture of a medicament for modulating the interaction between SIRPa and CD47 in a subject.
  • the disclosure provides a method of enhancing myeloid cell phagocytosis in a patient comprising administering to the patient an anti-SIRPa antibody or antigen-binding fragment thereof in an amount sufficient to enhance an immune response in the patient.
  • the disclosure provides an anti-SIRPa antibody or antigenbinding fragment thereof for use in enhancing myeloid cell activity in a patient.
  • the disclosure provides the use of an anti-SIRPa antibody or antigen-binding fragment thereof in the manufacture of a medicament for enhancing myeloid cell phagocytosis in a patient.
  • the disclosure provides a method of treating a SIRPa pathway disease ordisorder in a patient comprising administering to the patient an anti-SIRPa antibody or antigen-binding fragment thereof according to the present disclosure.
  • the disclosure provides an anti-SIRPa antibody or antigen-binding fragment thereof for use in treating or preventing cancer, inflammatory disease, autoimmune disease, respiratory disease, infectious disease or fibrosis in a patient.
  • the disclosure provides the use of an anti-SIRPa antibody or antigen-binding fragment thereof in the manufacture of a medicament for treating or preventing cancer, inflammatory disease, autoimmune disease, respiratory disease, infectious disease or fibrosis in a subject.
  • the disclosure provides a method of treating or preventing one of the above diseases or disorders in a patient comprising administering to the patient an anti-SIRPa antibody or antigen-binding fragment thereof according to the disclosure.
  • the disclosure provides an anti-SIRPa antibody or antigenbinding fragment thereof for use in treating or preventing one of the above diseases or disorders in a patient.
  • the disclosure provides the use of an anti-SIRPa antibody or antigen-binding fragment thereof in the manufacture of a medicament fortreating and/or preventing one of the above diseases or disorders in a patient.
  • the methods and uses described herein include the treatment of cancers comprising cancer cells that express antigens with low tumor specificity, such as CD47 and PD-L1 antigens.
  • the methods and uses described herein include the treatment of SIRPa-, CD47-, PD-L1 - or PD-1 -positive cancers.
  • the patient for treatment has been diagnosed with a SIRPa-positive cancer, a CD47-positive cancer, a PD-1-positive cancer, or a PD-L1 -positive cancer, in particular a cancer with solid tumors expressing or over-expressing SIRPa, CD47, PD-1 and/or PD-L1 .
  • a SIRPa-, CD47-, PD-L1 - or PD-1 -positive cancer is a cancer wherein tumor cells express SIRPa, CD47, PD-L1 and/or PD-1.
  • SIRPa, CD47-, PD-L1 - or PD-1 -positive tumor cell designates a tumor cell expressing SIRPa, CD47, PD-L1 or PD-1 at its cell surface.
  • a cancer may be classified in the subset of SIRPa-, CD47-, PD-L1- or PD-1 -positive cancer by flow cytometry evaluation using a primary mouse monoclonal antibody directed against SIRPa, CD47, PD-1 or PD-L1 , a secondary antibody and a kit for quantitative determination of cell surface antigens.
  • a SIRPa- , CD47-, PD-L1 - or PD-1 -positive cancer is defined by a Specific Antibody-Binding Capacity (SABC) strictly superior to zero %.
  • SABC Specific Antibody-Binding Capacity
  • the methods and uses described herein include treatment of cancer, including both primary and metastatic cancers, such as cancer from the bladder, blood, bone, bone marrow, brain, breast, colon, oesophagus, gastrointestinal, gum, head, kidney, liver, lung, nasopharynx, neck, ovary, prostate, skin, stomach, testis, tongue, or uterus.
  • primary and metastatic cancers such as cancer from the bladder, blood, bone, bone marrow, brain, breast, colon, oesophagus, gastrointestinal, gum, head, kidney, liver, lung, nasopharynx, neck, ovary, prostate, skin, stomach, testis, tongue, or uterus.
  • methods and uses described herein include treatment of ovarian cancer, pancreas cancer, Vater’s ampulla cancer, Micro Satellite Stable (MSS) cancer, Micro Satellite Instable (MSI) cancer, colorectal cancer, in particular MSI and MSS colorectal cancers, fibrolamellar cancer, breast cancer, melanoma, kidney cancer, lung cancer, in particular nonsmall cell lung cancer (NSCLC), head and neck cancer, in particular head and neck squamous cell carcinoma (HNSCC), gastric cancer and hepatocellular carcinoma cancer.
  • the methods and uses described herein include treatment of a cancer with solid tumors, in particular with advanced solid tumors.
  • the cancer with solid tumors does not contain any liquid or cysts.
  • the solid tumor is a sarcoma.
  • the solid tumor is a carcinoma.
  • the methods and uses described herein include treatment of a cancer in a patient who has ovarian cancer, pancreas cancer, Vater’s ampulla cancer, Micro Satellite Stable (MSS) cancer, Micro Satellite Instable (MSI) cancer, colorectal cancer, in particular MSI and MSS colorectal cancers, fibrolamellar cancer, breast cancer, melanoma, kidney cancer, lung cancer, in particular non-small cell lung cancer (NSCLC), head and neck cancer, in particular head and neck squamous cell carcinoma (HNSCC), gastric cancer or hepatocellular carcinoma cancer, the cancer being positive to SIRPa, PD-L1 or PD1 as described herein.
  • MSS Micro Satellite Stable
  • MSI Micro Satellite Instable
  • colorectal cancer in particular MSI and MSS colorectal cancers
  • fibrolamellar cancer breast cancer, melanoma
  • kidney cancer kidney cancer
  • lung cancer in particular non-small cell lung cancer (NSCLC)
  • the methods and uses described herein include treatment of a patient who has been, prior to the use, treated for their cancer and has shown resistance to the treatment and/or disease progression despite being treated.
  • the prior treatment may encompass any standard or conventional treatment of cancer.
  • standard or conventional treatment refers to any treatment of cancer (drug, surgery, radiotherapy, etc.) usually administrated to a patient who suffers from cancer.
  • the patient has been treated with at least 1 , at least 2, at least 3, or at least 4 cancer treatments prior to the administration of the anti-SIRPa antibody or antigen-binding fragment thereof.
  • the patient has been treated with 1 , 2, 3, or 4 cancer treatments prior to the administration of the anti-SIRPa antibody or antigen-binding fragment thereof.
  • the methods and uses described herein include treatment of a patient who has been treated, is treated or will be treated with an immune checkpoint inhibitor.
  • the methods and uses described herein include treatment of a patient who has been treated with an immune checkpoint inhibitor or activator, such as with an anti-PD-1 or an anti-PD-L1 antibody, and did not positively respond to the administration of the immune checkpoint inhibitor or activator (i.e. the patients show disease progression and/or do not show disease regression).
  • an immune checkpoint inhibitor or activator such as with an anti-PD-1 or an anti-PD-L1 antibody
  • the methods and uses described herein include monotherapy or combination therapy for the treatment of a patient as described herein.
  • the methods and uses described herein include treatment of a patient who has not been treated, is not treated or will not be treated with an immune checkpoint inhibitor.
  • the methods and uses described herein include treatment of a patient who has not been treated with an anti-PD-1 antibody or anti-PD-L1 antibody, in particular an anti-PD-1 antagonist antibody or anti-PD-L1 antagonist antibody prior to the administration of the anti-SIRPa antibody or antigen-binding fragment thereof.
  • the patient has at least one SIRPa V1 allele (i.e. is either homozygous and has two SIRPa V1 alleles or is heterozygous for SIRPa and has one SIRPa V1 allele).
  • the patient is homozygous for SIRPa and is SIRPa V1/SIRPa V1 .
  • the patient is heterozygous for SIRPa and is SIRPa V1 /SIRPa V2.
  • An anti-SIRPa antibody or an antigen-binding fragment thereof may be administered as a monotherapy or in combination with one or more additional therapeutic agents, such as state-of-the-art or standard-of-care compounds, such as e.g. cytostatic or cytotoxic substances, cell proliferation inhibitors, anti-angiogenic substances, steroids, immune modulators I checkpoint inhibitors, and the like.
  • additional therapeutic agents such as state-of-the-art or standard-of-care compounds, such as e.g. cytostatic or cytotoxic substances, cell proliferation inhibitors, anti-angiogenic substances, steroids, immune modulators I checkpoint inhibitors, and the like.
  • Cytostatic and/or cytotoxic active substances which may be administered in combination with an anti-SIRPa antibody or antigen-binding fragment thereof of the disclosure include, without being restricted thereto, hormones, hormone analogues and anti-hormones, aromatase inhibitors, LHRH agonists and antagonists, inhibitors of growth factors (e.g., platelet derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factors (IGF), human epidermal growth factor (HER, e.g.
  • growth factors e.g., platelet derived growth factor (PDGF), fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), insulin-like growth factors (IGF), human epidermal growth factor (HER, e.g.
  • HGF hepatocyte growth factor
  • anti-growth factor antibodies or anti-growth factor receptor antibodies and tyrosine kinase inhibitors such as, for example, cetuximab, gefitinib, afatinib, nintedanib, imatinib, lapatinib, bosutinib and trastuzumab
  • antimetabolites e.g., antifolates such as methotrexate, raltitrexed, pyrimidine analogues such as 5-fluorouracil (5-FU), gemcitabine, irinotecan, doxorubicin, TAS-102, capecitabine and gemcitabine, purine and adenosine analogues such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine (ara C), fludarabine); antitumor antibiotics (e
  • the anti-SIRPa antibody or antigen-binding fragment thereof is optionally administered in combination with an additional therapeutic agent.
  • the additional therapeutic agent may be a chemotherapeutic agent, an anti-PD-1 or PD-L1 antibody, an anti- CTLA4 antibody, a T cell engager, a CD137-agonist-anti-FAP bispecific antibody, a tumortargeting antibody, a VEGF-ANG2 bispecific antibody, a STING agonist, a MDM2 antagonist, or radiation therapy.
  • the anti-SIRPa antibody or an antigen-binding fragment thereof is administered in combination with an anti-PD-1 antibody, for example, nivolumab, pembrolizumab, pidilizumab, ezabenlimab, or atezolizumab.
  • an anti-PD-1 antibody for example, nivolumab, pembrolizumab, pidilizumab, ezabenlimab, or atezolizumab.
  • the anti- SIRPa antibody or an antigen-binding fragment thereof is administered in combination with an anti-PD-L1 antibody including, for example, avelumab or durvalumab.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered in combination with a tumor targeting antibody targeting HER2 (e.g., trastuzumab), EGFR (e.g., cetuximab, panitumumab), CD20 (e.g., rituximab, ofatumumab), or CD52 (e.g., alemtuzumab).
  • HER2 e.g., trastuzumab
  • EGFR e.g., cetuximab, panitumumab
  • CD20 e.g., rituximab, ofatumumab
  • CD52 e.g., alemtuzumab
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered in combination with two therapeutic agents.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered in combination with an anti-PD- 1 antibody (e.g., nivolumab, pembrolizumab, pidilizumab, ezabenlimab, or atezolizumab), or an anti-PD-L1 antibody (e.g., avelumab or durvalumab), and a tumor targeting antibody targeting HER2 (e.g., trastuzumab), EGFR (e.g., tetuximab, panitumumab), CD20 (e.g., rituximab, ofatumumab), or CD52 (e.g., alemtuzumab).
  • an anti-PD- 1 antibody e.g., nivolumab, pembrolizumab, pidilizumab
  • the one or more additional therapeutic agents are administered to a patient in a therapeutically effective amount.
  • the one or more additional therapeutic agents are administered at a dose of about 0.1 mg/kg to about 50 mg/kg, such as about 1 mg/kg to about 40 mg/kg, about 5 mg/kg to about 30 mg/kg, about 5 mg/kg to about 20 mg/kg, about 5 mg/kg to about 15 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 35 mg/kg, and/or about 50 mg/kg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof may be administered in combination with pembrolizumab to a subject.
  • the anti- SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 800 mg to about 3600 mg (e.g., about 800 mg, about 900 mg, about 1000 mg, about 1 100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg), about 1600 mg to about 3600 mg, about 2400 mg to about 3600 mg, or about 1600 mg to about 2400 mg, and pembrolizum
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg and pembrolizumab is administered to the subject at a dose of about 400 mg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1400 mg to about 1800 mg (e.g., about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg) and pembrolizumab is administered to the subject at a dose of about 400 mg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1400 mg to about 1500 mg and pembrolizumab is administered to the subject at a dose of about 400 mg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1500 mg to about 1600 mg and pembrolizumab is administered to the subject at a dose of about 400 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1600 mg to about 1700 mg and pembrolizumab is administered to the subject at a dose of about 400 mg. In some embodiments, the anti- SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1700 mg to about 1800 mg and pembrolizumab is administered to the subject at a dose of about 400 mg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg and pembrolizumab is administered to the subject at a dose of about 400 mg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1400 mg and pembrolizumab is administered intravenously to the subject at a dose of about 400 mg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1500 mg and pembrolizumab is administered intravenously to the subject at a dose of about 400 mg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1600 mg and pembrolizumab is administered intravenously to the subject at a dose of about 400 mg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1700 mg and pembrolizumab is administered intravenously to the subject at a dose of about 400 mg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1800 mg and pembrolizumab is administered intravenously to the subject at a dose of about 400 mg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of at least 800 mg to at least 3600 mg (e.g., at least 800 mg, at least 900 mg, at least 1000 mg, at least 1100 mg, at least 1200 mg, at least 1300 mg, at least 1400 mg, at least 1500 mg, at least 1600 mg, at least 1700 mg, at least
  • 1800 mg at least 1900 mg, at least 2000 mg, at least 2100 mg, at least 2200 mg, at least
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of at least 800 mg, at least 900 mg, at least 1000 mg, at least 1100 mg, at least 1200 mg, at least 1300 mg, at least 1400 mg, at least 1500 mg, at least 1600 mg, at least 1700 mg, at least 1800 mg, at least 1900 mg, at least 2000 mg, at least 2100 mg, at least 2200 mg, at least 2300 mg, at least 2400 mg, at least 2500 mg, at least 2600 mg, at least 2700 mg, at least 2800 mg, at least 2900 mg, at least 3000 mg, at least 3100 mg, at least 3200 mg, at least 3300 mg, at least 3400 mg, at least 3500 mg, or at least 3600 mg and pembrolizumab is administered to the subject at a dose of at least 400 mg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of at least 1400 mg to at least 1800 mg (e.g., at least 1400 mg, at least 1500 mg, at least 1600 mg, at least 1700 mg, or at least 1800 mg) and pembrolizumab is administered to the subject at a dose of at least 400 mg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of at least 1400 mg to at least 1500 mg and pembrolizumab is administered to the subject at a dose of at least 400 mg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of at least 1500 mg to at least 1600 mg and pembrolizumab is administered to the subject at a dose of at least 400 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of at least 1500 mg to at least 1600 mg and pembrolizumab is administered to the subject at a dose of at least 400 mg. In some embodiments, the anti- SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of at least 1600 mg to at least 1700 mg and pembrolizumab is administered to the subject at a dose of at least 400 mg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of at least 1700 mg to at least 1800 mg and pembrolizumab is administered to the subject at a dose of at least 400 mg. In some embodiments, the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of at least 1400 mg, at least 1500 mg, at least 1600 mg, at least 1700 mg, or at least 1800 mg and pembrolizumab is administered to the subject at a dose of at least 400 mg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of at least 1400 mg and pembrolizumab is administered intravenously to the subject at a dose of at least 400 mg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of at least 1500 mg and pembrolizumab is administered intravenously to the subject at a dose of at least 400 mg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of at least 1600 mg and pembrolizumab is administered intravenously to the subject at a dose of at least 400 mg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of at least 1700 mg and pembrolizumab is administered intravenously to the subject at a dose of at least 400 mg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of at least 1800 mg and pembrolizumab is administered intravenously to the subject at a dose of at least 400 mg.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered at a dosing cycle (administration interval) of about once every 2 weeks (Q2W) to about once every 6 weeks (Q6W) (e.g., about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), or about once every 6 weeks (Q6W)) and pembrolizumab is administered at a dosing cycle (administration interval) of about once every 3 weeks (Q3W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered at a dosing cycle (administration interval) of about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), or about once every 6 weeks (Q6W) and pembrolizumab is administered at a dosing cycle (administration interval) of about once every 3 weeks (Q3W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered at a dosing cycle (administration interval) of about once every 2 weeks (Q2W) to about once every 6 weeks (Q6W) (e.g., about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), or about once every 6 weeks (Q6W)) and pembrolizumab is administered at a dosing cycle (administration interval) of about once every 6 weeks (Q6W).
  • a dosing cycle administration interval
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered at a dosing cycle (administration interval) of about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), or about once every 6 weeks (Q6W) and pembrolizumab is administered at a dosing cycle (administration interval) of about once every 6 weeks (Q6W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof and pembrolizumab are administered at a dosing cycle (administration interval) of about once every 3 weeks (Q3W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof and pembrolizumab are administered at a dosing cycle (administration interval) of about once every 6 weeks (Q6W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered at a dose of about 800 mg to about 3600 mg (e.g., about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg), about 1600 mg to about 3600 mg, about 2400 mg to about 3600 mg, or about 1600 mg to about 2400 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W) to about once every 6 weeks (Q6W) (e.g., about once every
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered at a dose of about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), or about once every 6 weeks (Q6W) and pembrolizumab is administered at a dose of about 400 mg at a dosing cycle (administration
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered at a dose of about 800 mg to about 3600 mg (e.g., about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg), about 1600 mg to about 3600 mg, about 2400 mg to about 3600 mg, or about 1600 mg to about 2400 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W) to about once every 6 weeks (Q6W) (e.g., about once every
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered at a dose of about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), or about once every 6 weeks (Q6W) and pembrolizumab is administered at a dose of about 400 mg at a dosing cycle (administration
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered at a dose of about 1400 mg to about 1800 mg (e.g., about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg) at a dosing cycle (administration interval) of about once every 2 weeks (Q2W) to about once every 6 weeks (Q6W) (e.g., about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), or about once every 6 weeks (Q6W)) and pembrolizumab is administered at a dose of about 400 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W).
  • a dosing cycle administration interval
  • the anti- SIRPa antibody or antigen-binding fragment thereof is administered at a dose of about 1400 mg to about 1500 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W) to about once every 6 weeks (Q6W) (e.g., about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), or about once every 6 weeks (Q6W)) and pembrolizumab is administered at a dose of about 400 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W).
  • a dosing cycle administration interval
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered at a dose of about 1500 mg to about 1600 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W) to about once every 6 weeks (Q6W) (e.g., about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), or about once every 6 weeks (Q6W)) and pembrolizumab is administered at a dose of about 400 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W).
  • a dosing cycle administration interval
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered at a dose of about 1600 mg to about 1700 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W) to about once every 6 weeks (Q6W) (e.g., about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), or about once every 6 weeks (Q6W)) and pembrolizumab is administered at a dose of about 400 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W).
  • a dosing cycle administration interval
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered at a dose of about 1700 mg to about 1800 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W) to about once every 6 weeks (Q6W) (e.g., about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), or about once every 6 weeks (Q6W)) and pembrolizumab is administered at a dose of about 400 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W).
  • a dosing cycle administration interval
  • the anti-SIRPa antibody or antigenbinding fragment thereof is administered at a dose of about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), or about once every 6 weeks (Q6W) and pembrolizumab is administered at a dose of about 400 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered at a dose of about 1400 mg to about 1800 mg (e.g., about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg) at a dosing cycle (administration interval) of about once every 2 weeks (Q2W) to about once every 6 weeks (Q6W) (e.g., about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), or about once every 6 weeks (Q6W)) and pembrolizumab is administered at a dose of about 400 mg at a dosing cycle (administration interval) of about once every 6 weeks (Q6W).
  • a dosing cycle administration interval
  • the anti- SIRPa antibody or antigen-binding fragment thereof is administered at a dose of about 1400 mg to about 1500 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W) to about once every 6 weeks (Q6W) (e.g., about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), or about once every 6 weeks (Q6W)) and pembrolizumab is administered at a dose of about 400 mg at a dosing cycle (administration interval) of about once every 6 weeks (Q6W).
  • a dosing cycle administration interval
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered at a dose of about 1500 mg to about 1600 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W) to about once every 6 weeks (Q6W) (e.g., about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), or about once every 6 weeks (Q6W)) and pembrolizumab is administered at a dose of about 400 mg at a dosing cycle (administration interval) of about once every 6 weeks (Q6W).
  • a dosing cycle administration interval
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered at a dose of about 1600 mg to about 1700 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W) to about once every 6 weeks (Q6W) (e.g., about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), or about once every 6 weeks (Q6W)) and pembrolizumab is administered at a dose of about 400 mg at a dosing cycle (administration interval) of about once every 6 weeks (Q6W).
  • a dosing cycle administration interval
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered at a dose of about 1700 mg to about 1800 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W) to about once every 6 weeks (Q6W) (e.g., about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), or about once every 6 weeks (Q6W)) and pembrolizumab is administered at a dose of about 400 mg at a dosing cycle (administration interval) of about once every 6 weeks (Q6W).
  • a dosing cycle administration interval
  • the anti-SIRPa antibody or antigenbinding fragment thereof is administered at a dose of about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W), about once every 3 weeks (Q3W), about once every 4 weeks (Q4W), about once every 5 weeks (Q5W), or about once every 6 weeks (Q6W) and pembrolizumab is administered at a dose of about 400 mg at a dosing cycle (administration interval) of about once every 6 weeks (Q6W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously at a dose of about 1400 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W) and pembrolizumab is administered intravenously at a dose of about 400 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously at a dose of about 1500 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W) and pembrolizumab is administered intravenously at a dose of about 400 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously at a dose of about 1600 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W) and pembrolizumab is administered intravenously at a dose of about 400 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously at a dose of about 1700 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W) and pembrolizumab is administered intravenously at a dose of about 400 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously at a dose of about 1800 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W) and pembrolizumab is administered intravenously at a dose of about 400 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously at a dose of about 1400 mg at a dosing cycle (administration interval) of about once every 6 weeks (Q6W) and pembrolizumab is administered intravenously at a dose of about 400 mg at a dosing cycle (administration interval) of about once every 6 weeks (Q6W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously at a dose of about 1500 mg at a dosing cycle (administration interval) of about once every 6 weeks (Q6W) and pembrolizumab is administered intravenously at a dose of about 400 mg at a dosing cycle (administration interval) of about once every 6 weeks (Q6W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously at a dose of about 1600 mg at a dosing cycle (administration interval) of about once every 6 weeks (Q6W) and pembrolizumab is administered intravenously at a dose of about 400 mg at a dosing cycle (administration interval) of about once every 6 weeks (Q6W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously at a dose of about 1700 mg at a dosing cycle (administration interval) of about once every 6 weeks (Q6W) and pembrolizumab is administered intravenously at a dose of about 400 mg at a dosing cycle (administration interval) of about once every 6 weeks (Q6W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously at a dose of about 1800 mg at a dosing cycle (administration interval) of about once every 6 weeks (Q6W) and pembrolizumab is administered intravenously at a dose of about 400 mg at a dosing cycle (administration interval) of about once every 6 weeks (Q6W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof may be administered in combination with pembrolizumab and cetuximab to a subject.
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 800 mg to about 3600 mg (e.g., about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg), about 1600 mg to about 3600 mg, about 2400 mg to about 3600 mg, or about 1600 mg to about 2400
  • the anti- SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg, pembrolizumab is administered to the subject at a dose of about 400 mg, and cetuximab is administered to the subject at a dose of about 500 mg/m 2 .
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1400 mg to about 1800 mg (e.g., about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, orabout 1800 mg), pembrolizumab is administered to the subject at a dose of about 400 mg, and cetuximab is administered to the subject at a dose of about 500 mg/m 2 .
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1400 mg to about 1500 mg, pembrolizumab is administered to the subject at a dose of about 400 mg, and cetuximab is administered to the subject at a dose of about 500 mg/m 2 .
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1500 mg to about 1600 mg
  • pembrolizumab is administered to the subject at a dose of about 400 mg
  • cetuximab is administered to the subject at a dose of about 500 mg/m 2 .
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1600 mg to about 1700 mg, pembrolizumab is administered to the subject at a dose of about 400 mg, and cetuximab is administered to the subject at a dose of about 500 mg/m 2 .
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1700 mg to about 1800 mg
  • pembrolizumab is administered to the subject at a dose of about 400 mg
  • cetuximab is administered to the subject at a dose of about 500 mg/m 2 .
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg, pembrolizumab is administered to the subject at a dose of about 400 mg, and cetuximab is administered to the subject at a dose of about 500 mg/m 2 .
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1400 mg
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 .
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1500 mg
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 .
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1600 mg
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 .
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1700 mg
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 .
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1800 mg
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 .
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 800 mg to about 3600 mg (e.g., about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg), about 1600 mg to about 3600 mg, about 2400 mg to about 3600 mg, or about 1600 mg to about 2400 mg, pembrolizumab is administered to the subject at a dose of about 400 mg, and cetuximab is administered to the subject at an initial dose of
  • the anti-SIRPa antibody or antigenbinding fragment thereof is administered to a subject at a dose of about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg, pembrolizumab is administered to the subject at a dose of about 400 mg, and cetuximab is administered to the subject at an initial dose of about 400 mg/m 2 and a subsequent dose at 250 mg/m 2 .
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1400 mg to about 1800 mg (e.g., about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, orabout 1800 mg), pembrolizumab is administered to the subject at a dose of about 400 mg, and cetuximab is administered to the subject at an initial dose of about 400 mg/m 2 and a subsequent dose at 250 mg/m 2 .
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1400 mg to about 1500 mg, pembrolizumab is administered to the subject at a dose of about 400 mg, and cetuximab is administered to the subject at an initial dose of about 400 mg/m 2 and a subsequent dose at 250 mg/m 2 .
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1500 mg to about 1600 mg
  • pembrolizumab is administered to the subject at a dose of about 400 mg
  • cetuximab is administered to the subject at an initial dose of about 400 mg/m 2 and a subsequent dose at 250 mg/m 2 .
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1600 mg to about 1700 mg, pembrolizumab is administered to the subject at a dose of about 400 mg, and cetuximab is administered to the subject at an initial dose of about 400 mg/m 2 and a subsequent dose at 250 mg/m 2 .
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1700 mg to about 1800 mg
  • pembrolizumab is administered to the subject at a dose of about 400 mg
  • cetuximab is administered to the subject at an initial dose of about 400 mg/m 2 and a subsequent dose at 250 mg/m 2 .
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg, pembrolizumab is administered to the subject at a dose of about 400 mg, and cetuximab is administered to the subject at an initial dose of about 400 mg/m 2 and a subsequent dose at 250 mg/m 2 .
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1400 mg
  • pembrolizumab is administered to the subject at a dose of about 400 mg
  • cetuximab is administered to the subject at an initial dose of about 400 mg/m 2 and a subsequent dose at 250 mg/m 2 .
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1500 mg
  • pembrolizumab is administered to the subject at a dose of about 400 mg
  • cetuximab is administered to the subject at an initial dose of about 400 mg/m 2 and a subsequent dose at 250 mg/m 2 .
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1600 mg
  • pembrolizumab is administered to the subject at a dose of about 400 mg
  • cetuximab is administered to the subject at an initial dose of about 400 mg/m 2 and a subsequent dose at 250 mg/m 2 .
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1700 mg
  • pembrolizumab is administered to the subject at a dose of about 400 mg
  • cetuximab is administered to the subject at an initial dose of about 400 mg/m 2 and a subsequent dose at 250 mg/m 2 .
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1800 mg
  • pembrolizumab is administered to the subject at a dose of about 400 mg
  • cetuximab is administered to the subject at an initial dose of about 400 mg/m 2 and a subsequent dose at 250 mg/m 2 .
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dosing cycle (administration interval) of about once every 3 weeks (Q3W) or about once every 6 weeks (Q6W), pembrolizumab is administered to the subject at a dosing cycle of about once every 3 weeks (Q3W) or about once every 6 weeks (Q6W), and cetuximab is administered to the subject at a dosing cycle of about once every 2 weeks (Q2W) or about once every week (Q1 W).
  • a dosing cycle administration interval
  • pembrolizumab is administered to the subject at a dosing cycle of about once every 3 weeks (Q3W) or about once every 6 weeks (Q6W)
  • cetuximab is administered to the subject at a dosing cycle of about once every 2 weeks (Q2W) or about once every week (Q1 W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dosing cycle (administration interval) of about once every 3 weeks (Q3W), pembrolizumab is administered to the subject at a dosing cycle of about once every 3 weeks (Q3W), and cetuximab is administered to the subject at a dosing cycle of about once every 2 weeks (Q2W).
  • a dosing cycle administration interval
  • pembrolizumab is administered to the subject at a dosing cycle of about once every 3 weeks (Q3W)
  • cetuximab is administered to the subject at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dosing cycle (administration interval) of about once every 6 weeks (Q6W), pembrolizumab is administered to the subject at a dosing cycle of about once every 6 weeks (Q6W), and cetuximab is administered to the subject at a dosing cycle of about once every 2 weeks (Q2W).
  • a dosing cycle administration interval
  • pembrolizumab is administered to the subject at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered to the subject at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dosing cycle (administration interval) of about once every 3 weeks (Q3W), pembrolizumab is administered to the subject at a dosing cycle of about once every 3 weeks (Q3W), and cetuximab is administered to the subject at a dosing cycle of about once every week (Q1 W).
  • a dosing cycle administration interval of about once every 3 weeks (Q3W)
  • pembrolizumab is administered to the subject at a dosing cycle of about once every 3 weeks (Q3W)
  • cetuximab is administered to the subject at a dosing cycle of about once every week (Q1 W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dosing cycle (administration interval) of about once every 6 weeks (Q6W), pembrolizumab is administered to the subject at a dosing cycle of about once every 6 weeks (Q6W), and cetuximab is administered to the subject at a dosing cycle of about once every week (Q1 W).
  • a dosing cycle administration interval of about once every 6 weeks (Q6W)
  • pembrolizumab is administered to the subject at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered to the subject at a dosing cycle of about once every week (Q1 W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 800 mg to about 3600 mg (e.g., about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg), about 1600 mg to about 3600 mg, about 2400 mg to about 3600 mg, or about 1600 mg to about 2400 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W) or about once every 6 weeks (Q6W), pembrolizuma
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 800 mg, about 900 mg, about 1000 mg, about 1 100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W) or about once every 6 weeks (Q6W), pembrolizumab is administered to the subject at a dose of about 400 mg at a dosing cycle of about once every 3 weeks (Q3W) or about once every 6 weeks (Q6W), and cetuxim
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 800 mg to about 3600 mg (e.g., about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, or about 3600 mg), about 1600 mg to about 3600 mg, about 2400 mg to about 3600 mg, or about 1600 mg to about 2400 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W), pembrolizumab is administered intravenously to a dosing cycle (administration interval
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 800 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 900 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1000 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1100 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1200 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1300 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1400 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1500 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W), pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W), and cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • a dosing cycle administration interval
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1600 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1700 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1800 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1900 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 2000 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 2100 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 2200 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 2300 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 2400 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 2500 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 2600 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 2700 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 2800 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 2900 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 3000 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 3100 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 3200 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 3300 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 3400 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 3500 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 3600 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1400 mg to about 1800 mg (e.g., about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg) at a dosing cycle (administration interval) of about once every 3 weeks (Q3W) or about once every 6 weeks (Q6W), pembrolizumab is administered to the subject at a dose of about 400 mg at a dosing cycle of about once every 3 weeks (Q3W) or about once every 6 weeks (Q6W), and cetuximab is administered to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W) or at an initial dose of about 400 mg/m 2 and a subsequent dose at about 250 mg/m 2 at a dosing cycle of about once every week (Q1W).
  • a dosing cycle administration interval
  • pembrolizumab is administered to the subject at a dose of
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1400 mg to about 1500 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W) or about once every 6 weeks (Q6W)
  • pembrolizumab is administered to the subject at a dose of about 400 mg at a dosing cycle of about once every 3 weeks (Q3W) or about once every 6 weeks (Q6W)
  • cetuximab is administered to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W) or at an initial dose of about 400 mg/m 2 and a subsequent dose at about 250 mg/m 2 at a dosing cycle of about once every week (Q1 W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1500 mg to about 1600 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W) or about once every 6 weeks (Q6W)
  • pembrolizumab is administered to the subject at a dose of about 400 mg at a dosing cycle of about once every 3 weeks (Q3W) or about once every 6 weeks (Q6W)
  • cetuximab is administered to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W) or at an initial dose of about 400 mg/m 2 and a subsequent dose at about 250 mg/m 2 at a dosing cycle of about once every week (Q1 W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1600 mg to about 1700 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W) or about once every 6 weeks (Q6W)
  • pembrolizumab is administered to the subject at a dose of about 400 mg at a dosing cycle of about once every 3 weeks (Q3W) or about once every 6 weeks (Q6W)
  • cetuximab is administered to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W) or at an initial dose of about 400 mg/m 2 and a subsequent dose at about 250 mg/m 2 at a dosing cycle of about once every week (Q1 W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1700 mg to about 1800 mg at a dosing cycle (administration interval) of
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered to a subject at a dose of about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W) or about once every 6 weeks (Q6W)
  • pembrolizumab is administered to the subject at a dose of about 400 mg at a dosing cycle of about once every 3 weeks (Q3W) or about once every 6 weeks (Q6W)
  • cetuximab is administered to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W) or at an initial dose of about 400 mg/m 2 and a subsequent dose at about 250 mg/m 2 at a dosing cycle of about once every week (Q1 W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1400 mg to about 1800 mg (e.g., about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg) at a dosing cycle (administration interval) of about once every 2 weeks (Q2W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1400 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1400 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 3 weeks (Q3W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1400 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 3 weeks (Q3W)
  • cetuximab is administered intravenously to the subject at an initial dose of about 400 mg/m 2 and a subsequent dose at about 250 mg/m 2 at a dosing cycle of about once every week (Q1 W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1400 mg at a dosing cycle (administration interval) of about once every 6 weeks (Q6W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1400 mg at a dosing cycle (administration interval) of about once every 6 weeks (Q6W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at an initial dose of about 400 mg/m 2 and a subsequent dose at about 250 mg/m 2 at a dosing cycle of about once every week (Q1 W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1500 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1500 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 3 weeks (Q3W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1500 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 3 weeks (Q3W)
  • cetuximab is administered intravenously to the subject at an initial dose of about 400 mg/m 2 and a subsequent dose at about 250 mg/m 2 at a dosing cycle of about once every week (Q1 W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1500 mg at a dosing cycle (administration interval) of about once every 6 weeks (Q6W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1500 mg at a dosing cycle (administration interval) of about once every 6 weeks (Q6W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at an initial dose of about 400 mg/m 2 and a subsequent dose at about 250 mg/m 2 at a dosing cycle of about once every week (Q1 W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1600 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1600 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 3 weeks (Q3W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1600 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 3 weeks (Q3W)
  • cetuximab is administered intravenously to the subject at an initial dose of about 400 mg/m 2 and a subsequent dose at about 250 mg/m 2 at a dosing cycle of about once every week (Q1 W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1600 mg at a dosing cycle (administration interval) of about once every 6 weeks (Q6W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1600 mg at a dosing cycle (administration interval) of about once every 6 weeks (Q6W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at an initial dose of about 400 mg/m 2 and a subsequent dose at about 250 mg/m 2 at a dosing cycle of about once every week (Q1 W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1700 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1700 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 3 weeks (Q3W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1700 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 3 weeks (Q3W)
  • cetuximab is administered intravenously to the subject at an initial dose of about 400 mg/m 2 and a subsequent dose at about 250 mg/m 2 at a dosing cycle of about once every week (Q1 W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1700 mg at a dosing cycle (administration interval) of about once every 6 weeks (Q6W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1700 mg at a dosing cycle (administration interval) of about once every 6 weeks (Q6W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at an initial dose of about 400 mg/m 2 and a subsequent dose at about 250 mg/m 2 at a dosing cycle of about once every week (Q1 W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1800 mg at a dosing cycle (administration interval) of about once every 2 weeks (Q2W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1800 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 3 weeks (Q3W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1800 mg at a dosing cycle (administration interval) of about once every 3 weeks (Q3W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 3 weeks (Q3W)
  • cetuximab is administered intravenously to the subject at an initial dose of about 400 mg/m 2 and a subsequent dose at about 250 mg/m 2 at a dosing cycle of about once every week (Q1 W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1800 mg at a dosing cycle (administration interval) of about once every 6 weeks (Q6W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at a dose of about 500 mg/m 2 at a dosing cycle of about once every 2 weeks (Q2W).
  • the anti-SIRPa antibody or antigen-binding fragment thereof is administered intravenously to a subject at a dose of about 1800 mg at a dosing cycle (administration interval) of about once every 6 weeks (Q6W)
  • pembrolizumab is administered intravenously to the subject at a dose of about 400 mg at a dosing cycle of about once every 6 weeks (Q6W)
  • cetuximab is administered intravenously to the subject at an initial dose of about 400 mg/m 2 and a subsequent dose at about 250 mg/m 2 at a dosing cycle of about once every week (Q1 W).
  • the one or more additional therapeutic agents are administered at a dose of about 100 mg to about 1000 mg, such as about 100 mg to about 800 mg, about 100 mg to about 600 mg, about 100 mg to about 500 mg, about 100 mg to about 400 mg, about 100 mg to about 300 mg, about 100 mg to about 200 mg, about 200 mg to about 300 mg, about 300 mg to about 400 mg, about 400 mg to about 500 mg, about 500 mg to about 600 mg, about 600 mg to about 700 mg, about 700 mg to about 800 mg, about 800 mg to about 900 mg, and/or about 900 mg to about 1000 mg.
  • about 100 mg to about 1000 mg such as about 100 mg to about 800 mg, about 100 mg to about 600 mg, about 100 mg to about 500 mg, about 100 mg to about 400 mg, about 100 mg to about 300 mg, about 100 mg to about 200 mg, about 200 mg to about 300 mg, about 300 mg to about 400 mg, about 400 mg to about 500 mg, about 500 mg to about 600 mg, about 600 mg to about 700 mg, about 700 mg to about 800 mg, about 800 mg to about
  • the one or more additional therapeutic agents are administered at a dose of about 100 mg, about 1 10 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about
  • the one or more additional therapeutic agents are administered more than one time to the patient.
  • the one or more additional therapeutic agents are administered in a dosing cycle, wherein the dosing cycle is the time period between one administration of the one or more additional therapeutic agents and the next administration of the one or more additional therapeutic agents, for example, between the first administration of the one or more additional therapeutic agents and the second administration of the one or more additional therapeutic agents.
  • the one or more additional therapeutic agents are administered several times according to a regular dosing cycle, i.e., the time period between each administration is the same, such every 21 days.
  • the one or more additional therapeutic agents are administered several times according to a changing dosing cycle, i.e., the time period between each administration may be lower or higher compared to the time period of the previous or next dosing cycle.
  • dosing cycles are interrupted by a treatment-free period of time. In an embodiment, dosing cycles are not interrupted by a treatment-free period of time.
  • each dosing cycle has a time period of about 7 days, about 14 days, about 21 days, about 28 days, about 35 days, about 42 days, about 49 days, or about 56 days.
  • the one or more additional therapeutic agents are administered to a patient on one or more of Day 1 , Day 2, Day 3, Day 4, Day 5, Day 6, or Day 7 of a dosing cycle and not administered on the remaining days of the dosing cycle.
  • the dose, as described herein, of the one or more additional therapeutic agents is administered to a patient on Day 1 of a 21 -day cycle and is not administered on days 2 to 21 of the 21 -day cycle.
  • the dose of the anti-SIRPa antibody or an antigen-binding fragment thereof and the dose of one or more additional therapeutic agents are administered to the patient on the same day.
  • a dose of about 100 mg to about 1000 mg such as about 100 mg to about 800 mg, about 100 mg to about 600 mg, about 100 mg to about 500 mg, about 100 mg to about 400 mg, about 100 mg to about 300 mg, about 100 mg to about 200 mg, about 200 mg to about 300 mg, about 300 mg to about 400 mg, about 400 mg to about 500 mg, about 500 mg to about 600 mg, about 600 mg to about 700 mg, about 700 mg to about 800 mg, about 800 mg to about 900 mg, and/or about 900 mg to about 1000 mg of an anti- PD1 antibody is administered to a patient on Day 1 of a 21 -day cycle and is not administered on Days 2 to 21 of the 21 -day cycle.
  • a dose of about 100 mg to about 1000 mg such as about 100 mg to about 800 mg, about 100 mg to about 600 mg, about 100 mg to about 500 mg, about 100 mg to about 400 mg, about 100 mg to about 300 mg, about 100 mg to about 200 mg, about 200 mg to about 300 mg, about 300 mg to about 400 mg, about 400 mg to about 500 mg, about 500 mg to about 600 mg, about 600 mg to about 700 mg, about 700 mg to about 800 mg, about 800 mg to about 900 mg, and/or about 900 mg to about 1000 mg of ezabenlimab is administered to a patient on Day 1 of a 21 -day cycle and is not administered on days 2 to 21 of the 21 -day cycle.
  • a dose of about 240 mg ezabenlimab is administered to a patient on Day 1 of a 21 -day cycle and is not administered on Days 2 to 21 of the 21 -day cycle.
  • a dose of about 200 mg, about 600 mg, about 1200 mg, about 1600 mg, about 2400 mg, or about 3500 mg of the anti-SIRPa antibody or an antigen-binding fragment thereof, and a dose of about 240 mg ezabenlimab are administered to a patient on Day 1 of a 21-day cycle and are not administered on Days 2 to 21 of the 21-day cycle.
  • a dose of about 200 mg of the anti-SIRPa antibody or an antigen-binding fragment thereof, and a dose of about 240 mg ezabenlimab are administered to a patient on Day 1 of a 21-day cycle and are not administered on Days 2 to 21 of the 21-day cycle.
  • a dose of about 600 mg of the anti-SIRPa antibody or an antigen-binding fragment thereof, and a dose of about 240 mg ezabenlimab are administered to a patient on Day 1 of a 21-day cycle and are not administered on Days 2 to 21 of the 21-day cycle.
  • a dose of about 1200 mg of the anti-SIRPa antibody or an antigen-binding fragment thereof, and a dose of about 240 mg ezabenlimab are administered to a patient on Day 1 of a 21-day cycle and are not administered on Days 2 to 21 of the 21-day cycle.
  • a dose of about 1600 mg of the anti-SIRPa antibody or an antigen-binding fragment thereof, and a dose of about 240 mg ezabenlimab are administered to a patient on Day 1 of a 21-day cycle and are not administered on Days 2 to 21 of the 21-day cycle.
  • a dose of about 2400 mg of the anti-SIRPa antibody or an antigen-binding fragment thereof, and a dose of about 240 mg ezabenlimab are administered to a patient on Day 1 of a 21-day cycle and are not administered on Days 2 to 21 of the 21-day cycle.
  • a dose of about 3500 mg of the anti-SIRPa antibody or an antigen-binding fragment thereof, and a dose of about 240 mg ezabenlimab are administered to a patient on Day 1 of a 21-day cycle and are not administered on Days 2 to 21 of the 21 -day cycle.
  • Various delivery systems are known and can be used to administerthe anti-SIRPa antibody or an antigen-binding fragment thereof.
  • Methods of introduction include but are not limited to intravitreal, eye drops, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes.
  • the anti-SIRPa antibody or an antigenbinding fragment thereof can be administered, for example by infusion, bolus or injection, and can be administered together with other biologically active agents. Administration can be systemic or local. Formulations for such injections may be prepared in, for example, prefilled syringes that include an anti-SIRPa antibody or an antigen-binding fragment thereof.
  • the anti-SIRPa antibody of the disclosure is formulated into pharmaceutical compositions appropriate to facilitate administration to animals or humans.
  • Typical formulations of the binding molecule or antibody molecule described herein can be prepared by mixing the binding molecule or antibody molecule with physiologically acceptable carriers, excipients or stabilizers, in the form of lyophilized or otherwise dried formulations or aqueous solutions or aqueous or non-aqueous suspensions. Carriers, excipients, modifiers or stabilizers are nontoxic at the dosages and concentrations employed.
  • the pharmaceutical composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous or subcutaneous administration to a subject.
  • compositions for administration by injection are solutions in sterile isotonic aqueous buffer.
  • the pharmaceutical composition can also include a solubilizing agent and a local anesthetic such as lignocaine to ease pain at the site of the injection.
  • the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachet indicating the quantity of active agent.
  • the pharmaceutical is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • an ampoule ofsterile waterfor injection or saline can be provided so that the ingredients can be mixed prior to administration.
  • the pharmaceutical composition can be provided as a pharmaceutical kit comprising (a) a container containing an anti-SIRPa antibody or an antigen-binding fragment thereof in lyophilized form and (b) a second container containing a pharmaceutically acceptable diluent (e.g., sterile water) for injection.
  • a pharmaceutically acceptable diluent e.g., sterile water
  • the pharmaceutically acceptable diluent can be used for reconstitution or dilution of the lyophilized anti-SIRPa antibody or antigenbinding fragment thereof.
  • Optionally associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
  • a single dose of 600 mg, 1200 mg, 1600 mg, 2400 mg, or 3600 mg of antibody A10 was administered by intravenous (i.v.) injection to each of three adult human subjects.
  • 6 mg/kg, 12 mg/kg, 18 mg/kg, 24 mg/kg, or 36 mg/kg was administered by i.v. injection to each of 6 to 12 adult human subjects.
  • Blood was collected from each of the subjects from 0 to 504 hours following administration. The concentration of each antibody in the serum was measured by ELISA to assess pharmacokinetics. Briefly, blood was allowed to clot at room temperature for at least 30 minutes. Samples were centrifuged at about 1500- 2000xg at 2-8°C. within one hour of collection. Blood was collected as stored at -60° C to -80° C until analysis.
  • Serum concentration-time profiles (e.g., see FIGS. 3A-3C) were used to estimate the following PK parameters using a two-compartment analysis: antibody clearance (CL), volume (V), peripheral volume, Q, V max , and K m .
  • CL antibody clearance
  • V volume
  • Q volume
  • V max peripheral volume
  • K m K m
  • the modeling approach included a population PK-PD (serum concentration and peripheral target engagement (TE)) component and a minimal physiologically-based pharmacokinetic (mPBPK) (PET data-tumor lesion activity) component. Proof of clinical principle was reached by 24 mg/kg antibody X1 treatment. Subsequently, the mPBPK model was used to predict antibody A10 tumor exposure and target engagement at dose regimens that match antibody X1 target engagement.
  • TE serum concentration and peripheral target engagement
  • mPBPK minimal physiologically-based pharmacokinetic
  • Antibody 10 L/h 0.0243 0.0142 - 0.0416
  • Example 2 A Phase I Study of Antibody X1 in Patients with Advanced Cancer
  • the antibody X1 was tested in an open-label, non-randomized, Phase I study in four patients with advanced cancer (two head and neck, one non-small cell lung cancer, and one melanoma) without standard therapy options.
  • the primary objective was to observe distribution of antibody X1 in tumor lesions and normal tissues and organs in patients who also received ezabenlimab.
  • Tumors were identified by conventional imaging (18F-FDG PET fortumor glucose uptake and CT) and were assessed visually on the 89 Zr-PET for radioactive uptake exceeding that in tissues without target expression. Quantitative assessment was done based on the net influx rate, Ki, determined by Patlak linearization. This model assumes that the volume of the tumor lesion and the contrast to background does not change between the three PET-scans in one imaging cycle. Tumors that resulted in unreliable Patlak linearization (negative volume of distribution or r ⁇ 0.9) were excluded from analysis. Saturation was demonstrated by a decrease in Ki by the treatment dose compared to the tracer dose.
  • the Ki values for the tracer dose ranged between 1 .3*10-3[h-1 ] and 3.7 *10-3[h-1 ], which demonstrated a Ki higher than 0.7*10-3[h-1 ] (non-tumor reference Ki) for all lesions.
  • the Ki values for the treatment dose ranged between 0.7*10-3[h-1] and 2.1 *10-3[h-1], The Ki for the treatment dose was lower than for the tracer dose in all but one lesion.
  • Example 3 A Phase I Study of Antibody A10 in Patients with Advanced Solid Tumors
  • the anti-SIRPa antibody was tested in a two-step, open label, Phase I study in patients with advanced solid tumors. Part 1 studied a dose escalation monotherapy of the anti- SIRPa antibody and Part 2 studied a dose expansion of the anti-SIRPa antibody in combination with ezabenlimab.
  • the primary objectives were to determine the maximum tolerated dose for the anti-SIRPa antibody monotherapy and the anti-SIRPa antibody in combination with ezabenlimab and to determine a recommended dose for expansion based on all available data, including safety, preliminary efficacy, and pharmacokinetics/pharmacodynamics.
  • the primary endpoint was the occurrence of dose-limiting toxicities during the maximum tolerated dose evaluation period.
  • the secondary endpoints were the occurrence of adverse events and dose-limiting toxicities during the on-treatment period and efficacy according to RECIST (response evaluation criteria in solid tumors) v1.1 and investigator assessment.
  • Patient demographic and disease characteristics are provided in the following table (ECOG PS: Eastern Cooperative Oncology Group performance score).
  • ECOG PS Eastern Cooperative Oncology Group performance score.
  • Example 4 A Phase lb Study of Antibody A10 in Patients with Metastatic or Unresectable, Recurrent Head and Neck Squamous Cell Carcinoma (HNSCC)
  • This Example describes a Phase lb open label, randomized clinical study to evaluate the safety and efficacy of antibody A10 in combination with pembrolizumab and cetuximab as a first-in line therapy for patients with HNSCC whose tumors express PD-1. Patients will undergo a screening period, a treatment period of up to approximately 24 months, and a follow-up period of approximately 1 year after last dose administration of antibody A10. The study will include approximately 90 participants.
  • Patients will be included in the study if they have histologically confirmed metastatic or unresectable HNSCC and PD-L1 positive results (CPS > 1 by an FDA-approved test). Prior biopsy results obtained not more than 6 months prior to screening could be accepted if a patient has results of PD-L1 expression. Patients will not be eligible for participation in the study if they:
  • HNSCC suitable for local therapy with curative intent
  • NPC Nasopharyngeal carcinoma
  • tumour location necessitating an urgent therapeutic intervention (e.g., palliative care, surgery or radiation therapy, such as spinal cord compression, other compressive mass, uncontrolled painful lesion, bone fracture);
  • an urgent therapeutic intervention e.g., palliative care, surgery or radiation therapy, such as spinal cord compression, other compressive mass, uncontrolled painful lesion, bone fracture;
  • autoimmune disease or a documented history of autoimmune disease that requires systemic treatment, i.e. corticosteroids or immunosuppressive drugs (patients with vitiligo, resolved childhood asthma/atopy, alopecia, or any chronic skin condition that does not require systemic therapy; patients with autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone and/or controlled Type 1 diabetes mellitus on a stable insulin or antidiabetic medicines regimen are eligible);
  • DKA diabetic ketoacidosis
  • NASH New York Heart Association
  • unstable heart disease e.g. coronary artery disease with unstable angina or myocardial infarction within 6 months before trial drug administration
  • ECG electrocardiogram
  • cardiac dysrhythmia > Grade 2, NCI CTCAE v5.0
  • significant ventricular arrhythmia such as persistent ventriculartachycardia and/or ventricular fibrillation or severe conduction disorders, such as atrio-ventricular block 2 and 3, sinoatrial block, or baseline QTcF interval > 480 milliseconds (ms);
  • HIV human immunodeficiency virus
  • [00321] Patients who meet the inclusion criteria will receive either antibody A10 in combination with pembrolizumab (Group 1 ), antibody A10 in combination with pembrolizumab and cetuximab (Group 2), or pembrolizumab monotherapy (Group 3).
  • Antibody A10 will be administered intravenously at a dose of 3600 mg every 3 weeks (Q3W)
  • pembrolizumab will be administered intravenously at a dose of 200 mg Q3W
  • cetuximab will be administered intravenously at a dose of 500 mg/m 2 every 2 weeks (Q2W) or at an initial dose of 400 mg/m 2 with a subsequent dose at 250 mg/m 2 every week (Q1 W).
  • the primary trial objectives are to investigate whether antibody A10 alone and antibody A10 in combination with pembrolizumab and cetuximab demonstrate preliminary efficacy compared to pembrolizumab alone and antibody A10 in combination with pembrolizumab.
  • the primary comparison will be made for all treated patients, regardless of adherence to the protocol or premature discontinuation of the trial treatment but will exclude the effects of any subsequent anti-cancer therapy started before progression.
  • the efficacy of antibody A10 will be assessed by evaluating tumor response according to RECIST v1.1 and iRECIST.
  • the primary endpoints include the objective response (OR) with confirmation, defined as the best overall response of complete response (CR) or partial response (PR), where best overall response is determined according to RECIST v1.1 by investigator’s assessment from randomization until the earliest of disease progression, death, or last evaluable tumor assessment before start of subsequent anti-cancer therapy, lost to follow-up or withdrawal of consent.
  • OR objective response
  • confirmation defined as the best overall response of complete response (CR) or partial response (PR)
  • best overall response is determined according to RECIST v1.1 by investigator’s assessment from randomization until the earliest of disease progression, death, or last evaluable tumor assessment before start of subsequent anti-cancer therapy, lost to follow-up or withdrawal of consent.
  • the secondary trial objectives include assessing the safety and tolerability of antibody A10 as measured by the proportion of patients with at least one adverse event (AE) and the efficacy of antibody A10 as determined by the overall survival after 12 months of treatment (OS12), progression free survival (PFS) and PFS after 6 months (PFS6), disease control (DC), and duration of response (DOR).
  • AE adverse event
  • OS12 overall survival after 12 months of treatment
  • PFS progression free survival
  • PFS PFS after 6 months
  • DC disease control
  • DOR duration of response
  • the study will include exploratory biomarker analyses to examine possible biomarkers for use in future patient selection.
  • analyses may include DNA/RNA sequencing and/or immunohistochemistry of tumor biopsies to determine SIRPa or CD47 expression or T cell and macrophage infiltration.
  • a stated range is understood to be any value between and at the limits of the stated range.
  • a range between 1 and 5 includes 1 , 2, 3, 4, and 5;
  • a range between 1 and 10 includes 1 , 2, 3, 4, 5, 6, 7, 8, 9, and 10;
  • a range between 1 and 100 includes 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87,

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente divulgation concerne le traitement du cancer à l'aide d'un anticorps anti-SIRPα (protéine régulatrice de signal alpha) ou d'un fragment de liaison à l'antigène de celui-ci. En particulier, la présente divulgation concerne une méthode d'utilisation et des utilisations d'un anticorps anti-SIRPα ou d'un fragment de liaison à l'antigène de celui-ci pour traiter le cancer, y compris dans un régime de traitement qui comprend éventuellement l'administration d'un agent thérapeutique supplémentaire.
PCT/IB2024/059746 2023-10-06 2024-10-04 Utilisation d'anticorps anti-sirp-alpha pour traiter le cancer Pending WO2025074328A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US202363542980P 2023-10-06 2023-10-06
US63/542,980 2023-10-06
US202463654781P 2024-05-31 2024-05-31
US63/654,781 2024-05-31

Publications (1)

Publication Number Publication Date
WO2025074328A1 true WO2025074328A1 (fr) 2025-04-10

Family

ID=93376483

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2024/059746 Pending WO2025074328A1 (fr) 2023-10-06 2024-10-04 Utilisation d'anticorps anti-sirp-alpha pour traiter le cancer

Country Status (2)

Country Link
TW (1) TW202535460A (fr)
WO (1) WO2025074328A1 (fr)

Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4179337A (en) 1973-07-20 1979-12-18 Davis Frank F Non-immunogenic polypeptides
US4301144A (en) 1979-07-11 1981-11-17 Ajinomoto Company, Incorporated Blood substitute containing modified hemoglobin
US4496689A (en) 1983-12-27 1985-01-29 Miles Laboratories, Inc. Covalently attached complex of alpha-1-proteinase inhibitor with a water soluble polymer
US4640835A (en) 1981-10-30 1987-02-03 Nippon Chemiphar Company, Ltd. Plasminogen activator derivatives
US4670417A (en) 1985-06-19 1987-06-02 Ajinomoto Co., Inc. Hemoglobin combined with a poly(alkylene oxide)
US4791192A (en) 1986-06-26 1988-12-13 Takeda Chemical Industries, Ltd. Chemically modified protein with polyethyleneglycol
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
WO1990005144A1 (fr) 1988-11-11 1990-05-17 Medical Research Council Ligands a domaine unique, recepteurs comprenant lesdits ligands, procedes pour leur production, et emploi desdits ligands et recepteurs
WO1996032478A1 (fr) 1995-04-14 1996-10-17 Genentech, Inc. Polypeptides modifies a demi-vie accrue
US6037454A (en) 1996-11-27 2000-03-14 Genentech, Inc. Humanized anti-CD11a antibodies
US6054297A (en) 1991-06-14 2000-04-25 Genentech, Inc. Humanized antibodies and methods for making them
US6407213B1 (en) 1991-06-14 2002-06-18 Genentech, Inc. Method for making humanized antibodies
WO2005077042A2 (fr) 2004-02-09 2005-08-25 Human Genome Sciences, Inc. Proteines hybrides d'albumine
WO2012092374A2 (fr) 2010-12-31 2012-07-05 Short Jay M Humanisation express d'anticorps
WO2022254379A1 (fr) 2021-06-04 2022-12-08 Boehringer Ingelheim International Gmbh Anticorps anti-sirp-alpha

Patent Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4179337A (en) 1973-07-20 1979-12-18 Davis Frank F Non-immunogenic polypeptides
US4301144A (en) 1979-07-11 1981-11-17 Ajinomoto Company, Incorporated Blood substitute containing modified hemoglobin
US4640835A (en) 1981-10-30 1987-02-03 Nippon Chemiphar Company, Ltd. Plasminogen activator derivatives
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US4496689A (en) 1983-12-27 1985-01-29 Miles Laboratories, Inc. Covalently attached complex of alpha-1-proteinase inhibitor with a water soluble polymer
US4670417A (en) 1985-06-19 1987-06-02 Ajinomoto Co., Inc. Hemoglobin combined with a poly(alkylene oxide)
US4791192A (en) 1986-06-26 1988-12-13 Takeda Chemical Industries, Ltd. Chemically modified protein with polyethyleneglycol
WO1990005144A1 (fr) 1988-11-11 1990-05-17 Medical Research Council Ligands a domaine unique, recepteurs comprenant lesdits ligands, procedes pour leur production, et emploi desdits ligands et recepteurs
US6054297A (en) 1991-06-14 2000-04-25 Genentech, Inc. Humanized antibodies and methods for making them
US6407213B1 (en) 1991-06-14 2002-06-18 Genentech, Inc. Method for making humanized antibodies
WO1996032478A1 (fr) 1995-04-14 1996-10-17 Genentech, Inc. Polypeptides modifies a demi-vie accrue
US6037454A (en) 1996-11-27 2000-03-14 Genentech, Inc. Humanized anti-CD11a antibodies
WO2005077042A2 (fr) 2004-02-09 2005-08-25 Human Genome Sciences, Inc. Proteines hybrides d'albumine
WO2012092374A2 (fr) 2010-12-31 2012-07-05 Short Jay M Humanisation express d'anticorps
WO2022254379A1 (fr) 2021-06-04 2022-12-08 Boehringer Ingelheim International Gmbh Anticorps anti-sirp-alpha

Non-Patent Citations (43)

* Cited by examiner, † Cited by third party
Title
"Antibody Drug Discovery", vol. 4, 2012, article "Molecular medicine and medicinal chemistry"
"FcyR requirements leading to successful immunotherapy", IMMUNOL REV, vol. 268, no. 1, November 2015 (2015-11-01), pages 104 - 22
ALMAGRO ET AL., FRONTIERS IN BIOSCIENCE, vol. 13, 2008, pages 1619 - 1633
ALMAGRO ET AL., PROTEINS, vol. 79, 2011, pages 3050 - 3066
ALTSCHUL ET AL., J. MOL. BIOL., vol. 215, 1990, pages 403 - 410
ALTSCHUL ET AL., NUCLEIC ACIDS RES., vol. 25, 1997, pages 3389 - 3402
ANGEW, CHEM. INTL. ED. ENGL, vol. 33, pages 183 - 186
BRENNAN ET AL., SCIENCE, vol. 229, 1985, pages 81
BROOKE ET AL., J IMMUNOL., vol. 173, no. 4, 15 August 2004 (2004-08-15), pages 2562 - 70
BRUGGEMANN MTAUSSIG MJ: "Production of human antibody repertoires in transgenic mice", CURR OPIN BIOTECHNOL, vol. 8, no. 4, August 1997 (1997-08-01), pages 455 - 8
CARTER ET AL., BIO/TECHNOLOGY, vol. 10, 1992, pages 163 - 167
CHOTHIA ET AL., J. MOL. BIOL., vol. 186, 1985, pages 651 - 663
CHOTHIALESK, J. MOL. BIOL., vol. 196, 1987, pages 901 - 917
CLACKSON ET AL., NATURE, vol. 352, 1991, pages 624 - 628
D. MARKSH.R. HOOGENBOOMT.P. BONNERTJ. MCCAFFERTYA.D. GRIFFITHSG. WINTER: "J.Mol.Biol.", vol. 222, 1991, article "By-passing immunisation. Human antibodies from V-gene libraries displayed on phage", pages: 581 - 597
EDGE ET AL., ANAL. BIOCHEM., vol. 118, 1981, pages 131
HAKIMUDDIN ET AL., ARCH. BIOCHEM. BIOPHYS, vol. 259, 1987, pages 52
HATHERLEY D, 2008 IMMUNITY, vol. 29, no. 5, 14 November 2008 (2008-11-14), pages 675 - 8
HIGGINS ET AL., METHODS ENZYMOL., vol. 266, pages 383 - 402
JANICE M REICHERTEUGEN DHIMOLEA: "The future of antibodies as cancer drugs", DRUG DISCOV TODAY, vol. 17, no. 17-18, August 2012 (2012-08-01), pages 954 - 63, XP002713827, DOI: 10.1016/j.drudis.2012.04.006
KARLINALTSCHUL, PROC. NATL. ACAD. SCI. USA, vol. 87, 1990, pages 2264 - 2268
KARLINALTSCHUL, PROC. NATL. ACAD. SCI. USA, vol. 90, 1993, pages 5873 - 5877
KNAPPIK ET AL., J. MOL. BIOL., vol. 296, 2000, pages 57 - 86
KOHLER ET AL., NATURE, vol. 256, 1975, pages 495
KOTECKI N. ET AL: "983P Phase I dose escalation study in patients (pts) with advanced solid tumours receiving first-in-class BI 765063, a selective signal-regulatory protein [alpha] (SIRP[alpha]) inhibitor, in combination with ezabenlimab (BI 754091), a programmed cell death protein 1 (PD-1) inhibitor", ANNALS OF ONCOLOGY, vol. 32, 1 September 2021 (2021-09-01), pages S841 - S842, XP093239964, ISSN: 0923-7534, DOI: 10.1016/j.annonc.2021.08.1367 *
LEFRANC MP: "Unique database numbering system for immunogenetic analysis", IMMUNOL TODAY, vol. 18, 1997, pages 509, XP004093509, DOI: 10.1016/S0167-5699(97)01163-8
LIU ET AL., J MOL BIOL., vol. 365, no. 3, 19 January 2007 (2007-01-19), pages 680 - 93
LONBERG NHUSZAR D: "Human antibodies from transgenic mice", INT REV IMMUNOL, vol. 13, no. 1, 1995, pages 65 - 93
MABS, vol. 11, no. 6, August 2019 (2019-08-01), pages 1036 - 1052
MAIER ET AL., PROTEINS, vol. 82, 2014, pages 1599 - 1610
MARKS ET AL., J. MOL. BIOL., vol. 222, 1991, pages 581 - 597
MORIMOTO ET AL., JOURNAL OF BIOCHEMICAL AND BIOPHYSICAL METHODS, vol. 24, 1992, pages 107 - 117
MORRISON ET AL., PROC. NATL. ACAD. SCI. USA, vol. 81, 1984, pages 6851 - 6855
NORTH BLEHMANN ADUNBRACK RLJ: "A new clustering of antibody CDR loop conformations", J MOL BIOL., vol. 406, 2011, pages 228 - 56, XP028129711, DOI: 10.1016/j.jmb.2010.10.030
PEARSON, PROC. NATL. ACAD. SCI. USA, vol. 85, 1988, pages 2444 - 8
S. CARMENL. JERMUTUS: "Concepts in antibody phage display", BRIEFINGS IN FUNCTIONAL GENOMICS AND PROTEOMICS, vol. 1, no. 2, 2002, pages 189 - 203
SON JI ET AL: "Inhibition of the CD47-SIRP[alpha] axis for cancer therapy: A systematic review and meta-analysis of emerging clinical data", FRONTIERS IN IMMUNOLOGY, vol. 13, 11 November 2022 (2022-11-11), Lausanne, CH, XP093239939, ISSN: 1664-3224, DOI: 10.3389/fimmu.2022.1027235 *
TAKENAKA, NAT IMMUNOL, vol. 8, no. 12, December 2007 (2007-12-01), pages 1313 - 23
THOTAKURA ET AL., METH. ENZYMOL, vol. 138, 1987, pages 350
TORELLISROBOTTI, COMPUT. APPL. BIOSCI, vol. 113, 1994, pages 269 - 315
TREFFERS, EUR J IMMUNOL., vol. 48, no. 2, February 2018 (2018-02-01), pages 344 - 354
VARGAS-MADRAZO EPAZ-GARCIA E, J MOL RECOGNIT, vol. 16, no. 3, 2003, pages 113 - 120
ZAPATA ET AL., PROTEIN ENG, vol. 8, no. 10, 1995, pages 1057 - 1062

Also Published As

Publication number Publication date
TW202535460A (zh) 2025-09-16

Similar Documents

Publication Publication Date Title
US10532096B2 (en) Methods and compositions comprising a combination of a VEGF antagonist and an anti-CTLA-4 antibody
US11572412B2 (en) Anti-SIRP-alpha antibodies
CN116327924A (zh) 用于癌症治疗的单独fgfr2抑制剂或与免疫刺激剂的组合
JP2016006101A (ja) Ｄｌｌ４アンタゴニスト及び化学療法剤を用いたがんの治療方法
AU2020319899A1 (en) Combined cancer therapy of anti-galectin-9 antibodies and chemotherapeutics
US20240024317A1 (en) Cancer treatment using bosentan in combination with a checkpoint inhibitor
US20230192839A1 (en) Antibodies having conditional affinity and methods of use thereof
KR20240038008A (ko) 암 치료 방법 및 조성물
US20250084178A1 (en) Anti-cd39 antibodies and use thereof
WO2022109302A1 (fr) Anticorps anti-galectine-9 et leurs utilisations thérapeutiques
WO2025074328A1 (fr) Utilisation d'anticorps anti-sirp-alpha pour traiter le cancer
WO2023164872A1 (fr) Anticorps anti-cd39 et leur utilisation
CN117881699A (zh) 抗SIRPα抗体
WO2024041652A1 (fr) Méthodes de traitement du cancer
WO2025079039A1 (fr) Traitement à base d'anti-pd-1 avant et après chirurgie
TW202515614A (zh) 治療非小細胞肺癌之方法及組成物
RU2834309C2 (ru) Ингибиторы fgfr2 отдельно или в комбинации с иммуностимулирующими агентами в лечении рака

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24800938

Country of ref document: EP

Kind code of ref document: A1