THERAPEUTIC CD47 ANTIBODIES

• US 20180142019A1
• Filed: 01/15/2018
• Published: 05/24/2018
• Est. Priority Date: 10/21/2016
• Status: Abandoned Application

• Current Assignee: Arch Oncology, Inc.
• Original Assignee: Tioma Therapeutics, Inc.
• Inventors: MANNING, Pamela T., PURO, Robyn, ALMAGRO, Juan C., KARR, Robert W.
• Application Number:
  US15/871,802
• Publication Number:
  US 20180142019A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 5/38 of the suprarenal hormones
• CPC Class Codes: A61P 7/06 Antianaemics
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/33 Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/56 variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/73 Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/732 : Antibody-dependent cellular cytotoxicity [ADCC]
• CPC Class Codes: C07K 2317/734 : Complement-dependent cytotoxicity [CDC]
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Abstract

Provided are anti-CD47 monoclonal antibodies (anti-CD47 mAbs) with distinct functional profiles as described herein, methods to generate anti-CD47 mAbs, and to methods of using these anti-CD47 mAbs as therapeutics for the prevention and treatment of solid and hematological cancers, ischemia-reperfusion injury, cardiovascular diseases, autoimmune diseases, inflammatory diseases or as diagnostics for determining the level of CD47 in tissue samples.

Claims

1-101. -101. (canceled)

102. A monoclonal antibody, or an antigen binding fragment thereof, which:

a. binds to human CD47;

b. blocks SIRP (binding to human CD47;

c. increases phagocytosis of human tumor cells;

d. induces death of human tumor cells;

e. exhibits pH-dependent binding to human CD47 present on a cell; and

wherein the monoclonal antibody, or an antigen binding fragment thereof, further comprises one or more characteristics selected from the group consisting of;

i) causes no detectable agglutination of human red blood cells, or causes reduced agglutination of human red blood cells, and

ii) has reduced human red blood cell binding, or has minimal human red blood cell binding.

103. The monoclonal antibody, or antigen binding fragment thereof, of claim 102, wherein said monoclonal antibody, or an antigen binding fragment thereof, possesses one or more among the following characteristics:

causes an increase in cell surface calreticulin expression on human tumor cells;

causes an increase in adenosine triphosphate (ATP) release by human tumor cells;

causes an increase in high mobility group box 1 (HMGB1) release by human tumor cells;

causes an increase in annexin A1 release by human tumor cells;

causes an increase in Type I Interferon release by human tumor cells;

causes an increase in C-X-C Motif Chemokine Ligand 10 (CXCL10) release by human tumor cells;

causes an increase in cell surface protein disulfide-isomerase A3 (PDIA3) expression on human tumor cells;

causes an increase in cell surface heat shock protein 70 (HSP70) expression on human tumor cells; and

causes an increase in cell surface heat shock protein 90 (HSP90) expression on human tumor cells.

104. The monoclonal antibody, or antigen binding fragment thereof, of claim 102, wherein the antibody, or antigen binding fragment thereof, is a chimeric or humanized antibody;

or wherein the monoclonal antibody, or antigen binding fragment thereof cross-reacts with one or more species homologs of CD47.

105. The monoclonal antibody, or antigen binding fragment thereof, of claim 102, wherein the antibody, or antigen binding fragment thereof, causes no detectable agglutination of human red blood cells and has minimal human red blood cell binding.

106. The monoclonal antibody, or antigen binding fragment thereof, of claim 102, wherein the pH-dependent binding to human CD47 has a greater affinity for human CD47 at an acidic pH compared to physiological pH.

107. A method of treating a disease comprising an autoimmune disease, an autoinflammatory disease, an inflammatory disease, a cardiovascular disease, or a cancer in a subject, comprising administration of the monoclonal antibody or antigen-binding fragment thereof, of claim 102, wherein the subject comprises a human or companion/pet animal, a working animal, a sport animal, a zoo animal, or a valuable animal kept in captivity.

108. The method of claim 107, wherein the disease is selected from the group consisting of a leukemia, a lymphoma, ovarian cancer, breast cancer, endometrial cancer, colon cancer (colorectal cancer), rectal cancer, bladder cancer, urothelial cancer, lung cancer (non-small cell lung cancer, adenocarcinoma of the lung, squamous cell carcinoma of the lung), bronchial cancer, bone cancer, prostate cancer, pancreatic cancer, gastric cancer, hepatocellular carcinoma, gall bladder cancer, bile duct cancer, esophageal cancer, renal cell carcinoma, thyroid cancer, squamous cell carcinoma of the head and neck (head and neck cancer), testicular cancer, cancer of the endocrine gland, cancer of the adrenal gland, cancer of the pituitary gland, cancer of the skin, cancer of soft tissues, cancer of blood vessels, cancer of brain, cancer of nerves, cancer of eyes, cancer of meninges, cancer of oropharynx, cancer of hypopharynx, cancer of cervix, and cancer of uterus, glioblastoma, meduloblastoma, astrocytoma, glioma, meningioma, gastrinoma, neuroblastoma, melanoma, myelodysplastic syndrome, a sarcoma, ischemia-reperfusion injury, heart failure, arthritis, rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, Crohn'"'"'s disease, inflammatory bowel disease, ulcerative colitis, lupus, systemic lupus erythematous, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, Grave'"'"'s disease, Hashimoto'"'"'s thyroiditis, Addison'"'"'s disease, celiac disease, dermatomyositis, multiple sclerosis, myasthenia gravis, pernicious anemia, Sjogren syndrome, type I diabetes, vasculitis, uveitis, atherosclerosis, and ankylosing spondylitis.

109. A monoclonal antibody, or an antigen binding fragment thereof, which:

a. binds to human CD47;

b. blocks SIRPα

binding to human CD47;

c. increases phagocytosis of human tumor cells;

d. induces death of human tumor cells;

e. exhibits pH-dependent binding to human CD47 present on a cell;

f. exhibits reduced binding to a normal cell; and

wherein the monoclonal antibody, or an antigen binding fragment thereof, further comprises one or more characteristics selected from the group consisting of;

i) causes no detectable agglutination of human red blood cells, or causes reduced agglutination of human red blood cells; and

ii) has reduced human red blood cell binding, or has minimal human red blood cell binding.

110. The monoclonal antibody, or antigen binding fragment thereof, of claim 109, wherein said monoclonal antibody, or an antigen binding fragment thereof, further comprises one or more characteristics selected from the group consisting of:

causes an increase in cell surface calreticulin expression on human tumor cells;

causes an increase in adenosine triphosphate (ATP) release by human tumor cells;

causes an increase in high mobility group box 1 (HMGB1) release by human tumor cells;

causes an increase in annexin A1 release by human tumor cells;

causes an increase in Type I Interferon release by human tumor cells;

causes an increase in C-X-C Motif Chemokine Ligand 10 (CXCL10) release by human tumor cells;

causes an increase in cell surface protein disulfide-isomerase A3 (PDIA3) expression on human tumor cells;

causes an increase in cell surface heat shock protein 70 (HSP70) expression on human tumor cells; and

causes an increase in cell surface heat shock protein 90 (HSP90) expression on human tumor cells.

111. The monoclonal antibody, or antigen binding fragment thereof, of claim 109, wherein the antibody, or antigen binding fragment thereof, is a chimeric or humanized antibody;

or wherein the monoclonal antibody, or antigen binding fragment thereof cross-reacts with one or more species homologs of CD47.

112. The monoclonal antibody, or antigen binding fragment thereof, of claim 109, wherein the antibody, or antigen binding fragment thereof, causes no detectable agglutination of human red blood cells and has minimal human red blood cell binding.

113. The monoclonal antibody, or antigen binding fragment thereof, of claim 109, wherein the pH-dependent binding to CD47 has a greater affinity for CD47 at an acidic pH compared to physiological pH.

114. A method of treating a disease comprising an autoimmune disease, an autoinflammatory disease, an inflammatory disease, a cardiovascular disease, or a cancer in a subject, comprising administration of the monoclonal antibody or antigen-binding fragment thereof, of claim 109, wherein subject comprises a human or companion/pet animal, a working animal, a sport animal, a zoo animal, or a valuable animal kept in captivity.

115. The method of claim 114, wherein the disease is selected from the group consisting of a leukemia, a lymphoma, ovarian cancer, breast cancer, endometrial cancer, colon cancer (colorectal cancer), rectal cancer, bladder cancer, urothelial cancer, lung cancer (non-small cell lung cancer, adenocarcinoma of the lung, squamous cell carcinoma of the lung), bronchial cancer, bone cancer, prostate cancer, pancreatic cancer, gastric cancer, hepatocellular carcinoma, gall bladder cancer, bile duct cancer, esophageal cancer, renal cell carcinoma, thyroid cancer, squamous cell carcinoma of the head and neck (head and neck cancer), testicular cancer, cancer of the endocrine gland, cancer of the adrenal gland, cancer of the pituitary gland, cancer of the skin, cancer of soft tissues, cancer of blood vessels, cancer of brain, cancer of nerves, cancer of eyes, cancer of meninges, cancer of oropharynx, cancer of hypopharynx, cancer of cervix, and cancer of uterus, glioblastoma, meduloblastoma, astrocytoma, glioma, meningioma, gastrinoma, neuroblastoma, melanoma, myelodysplastic syndrome, a sarcoma, ischemia-reperfusion injury, heart failure, arthritis, rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, Crohn'"'"'s disease, inflammatory bowel disease, ulcerative colitis, lupus, systemic lupus erythematous, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, Grave'"'"'s disease, Hashimoto'"'"'s thyroiditis, Addison'"'"'s disease, celiac disease, dermatomyositis, multiple sclerosis, myasthenia gravis, pernicious anemia, Sjogren syndrome, type I diabetes, vasculitis, uveitis, atherosclerosis, and ankylosing spondylitis.

116. A monoclonal antibody, or an antigen binding fragment thereof, which binds to human CD47, wherein said monoclonal antibody, or an antigen binding fragment thereof, exhibits pH-dependent binding to CD47 present on a cell.

117. The monoclonal antibody, or an antigen binding fragment thereof, of claim 116, which:

a. binds to human CD47;

b. blocks SIRPα

binding to human CD47;

c. increases phagocytosis of human tumor cells; and

d. induces death of human tumor cells.

118. The monoclonal antibody, or antigen binding fragment thereof, of claim 116, wherein said monoclonal antibody, or an antigen binding fragment thereof, further comprises one or more characteristics selected from the group consisting of:

causes an increase in cell surface calreticulin expression on human tumor cells;

causes an increase in adenosine triphosphate (ATP) release by human tumor cells;

causes an increase in high mobility group box 1 (HMGB1) release by human tumor cells;

causes an increase in annexin A1 release by human tumor cells;

causes an increase in Type I Interferon release by human tumor cells;

causes an increase in C-X-C Motif Chemokine Ligand 10 (CXCL10) release by human tumor cells;

causes an increase in cell surface protein disulfide-isomerase A3 (PDIA3) expression on human tumor cells;

causes an increase in cell surface heat shock protein 70 (HSP70) expression on human tumor cells; and

causes an increase in cell surface heat shock protein 90 (HSP90) expression on human tumor cells.

119. The monoclonal antibody, or antigen binding fragment thereof, of claim 116, wherein the antibody, or antigen binding fragment thereof, is a chimeric or humanized antibody;

or

wherein the monoclonal antibody, or antigen binding fragment thereof cross-reacts with one or more species homologs of CD47.

120. The monoclonal antibody, or antigen binding fragment thereof, of claim 116, wherein the pH-dependent binding to CD47 has a greater affinity for CD47 at an acidic pH compared to physiological pH.

121. A method of treating a disease comprising an autoimmune disease, an autoinflammatory disease, an inflammatory disease, a cardiovascular disease, or a cancer in a subject, comprising administration of the monoclonal antibody or antigen-binding fragment thereof, of claim 116, wherein the subject comprises a human or companion/pet animal, a working animal, a sport animal, a zoo animal, or a valuable animal kept in captivity.

122. The method of claim 121, wherein the disease is selected from the group consisting of a leukemia, a lymphoma, ovarian cancer, breast cancer, endometrial cancer, colon cancer (colorectal cancer), rectal cancer, bladder cancer, urothelial cancer, lung cancer (non-small cell lung cancer, adenocarcinoma of the lung, squamous cell carcinoma of the lung), bronchial cancer, bone cancer, prostate cancer, pancreatic cancer, gastric cancer, hepatocellular carcinoma, gall bladder cancer, bile duct cancer, esophageal cancer, renal cell carcinoma, thyroid cancer, squamous cell carcinoma of the head and neck (head and neck cancer), testicular cancer, cancer of the endocrine gland, cancer of the adrenal gland, cancer of the pituitary gland, cancer of the skin, cancer of soft tissues, cancer of blood vessels, cancer of brain, cancer of nerves, cancer of eyes, cancer of meninges, cancer of oropharynx, cancer of hypopharynx, cancer of cervix, and cancer of uterus, glioblastoma, meduloblastoma, astrocytoma, glioma, meningioma, gastrinoma, neuroblastoma, melanoma, myelodysplastic syndrome, a sarcoma, ischemia-reperfusion injury, heart failure, arthritis, rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, Crohn'"'"'s disease, inflammatory bowel disease, ulcerative colitis, lupus, systemic lupus erythematous, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, Grave'"'"'s disease, Hashimoto'"'"'s thyroiditis, Addison'"'"'s disease, celiac disease, dermatomyositis, multiple sclerosis, myasthenia gravis, pernicious anemia, Sjogren syndrome, type I diabetes, vasculitis, uveitis, atherosclerosis, and ankylosing spondylitis.

123. The monoclonal antibody, or antigen binding fragment thereof, of claim 116, wherein the monoclonal antibody, or antigen binding fragment thereof, further exhibits reduced binding to a normal cell.

124. A monoclonal antibody, or an antigen binding fragment thereof, which binds to human CD47, wherein said monoclonal antibody, or an antigen binding fragment thereof, exhibits reduced binding to a normal cell.

125. The monoclonal antibody, or an antigen binding fragment thereof, of claim 124, which:

a. binds to human CD47;

b. blocks SIRPα

binding to human CD47;

c. increases phagocytosis of human tumor cells; and

d. induces death of human tumor cells.

126. The monoclonal antibody, or antigen binding fragment thereof, of claim 124, wherein the normal cell is selected from the group consisting of an endothelial cell, a skeletal muscle cell, an epithelial cell, a PBMC, a T cell, a red blood cell, a peripheral blood mononuclear cell, a human aortic endothelial cell, a human skeletal muscle cell, a human microvascular endothelial cell, a human renal tubular epithelial cell, a human peripherial blood CD3+ cell, and a human peripheral blood mononuclear cell.

127. The monoclonal antibody, or antigen binding fragment thereof, of claim 124, wherein said monoclonal antibody, or an antigen binding fragment thereof, further comprises one or more characteristics selected from the group consisting of:

causes an increase in cell surface calreticulin expression on human tumor cells;

causes an increase in adenosine triphosphate (ATP) release by human tumor cells;

causes an increase in high mobility group box 1 (HMGB1) release by human tumor cells;

causes an increase in annexin A1 release by human tumor cells;

causes an increase in Type I Interferon release by human tumor cells;

causes an increase in C-X-C Motif Chemokine Ligand 10 (CXCL10) release by human tumor cells;

causes an increase in cell surface protein disulfide-isomerase A3 (PDIA3) expression on human tumor cells;

causes an increase in cell surface heat shock protein 70 (HSP70) expression on human tumor cells; and

causes an increase in cell surface heat shock protein 90 (HSP90) expression on human tumor cells.

128. The monoclonal antibody, or antigen binding fragment thereof, of claim 124, wherein the antibody, or antigen binding fragment thereof, is a chimeric or humanized antibody;

or wherein the monoclonal antibody, or antigen binding fragment thereof cross-reacts with one or more species homologs of CD47.

129. A method of treating a disease comprising an autoimmune disease, an autoinflammatory disease, an inflammatory disease, a cardiovascular disease, or a cancer in a subject, comprising administration of the monoclonal antibody or antigen-binding fragment thereof, of claim 124, wherein the subject comprises a human or companion/pet animal, a working animal, a sport animal, a zoo animal, or a valuable animal kept in captivity.

130. The method of claim 129, wherein the disease is selected from the group consisting of a leukemia, a lymphoma, ovarian cancer, breast cancer, endometrial cancer, colon cancer (colorectal cancer), rectal cancer, bladder cancer, urothelial cancer, lung cancer (non-small cell lung cancer, adenocarcinoma of the lung, squamous cell carcinoma of the lung), bronchial cancer, bone cancer, prostate cancer, pancreatic cancer, gastric cancer, hepatocellular carcinoma, gall bladder cancer, bile duct cancer, esophageal cancer, renal cell carcinoma, thyroid cancer, squamous cell carcinoma of the head and neck (head and neck cancer), testicular cancer, cancer of the endocrine gland, cancer of the adrenal gland, cancer of the pituitary gland, cancer of the skin, cancer of soft tissues, cancer of blood vessels, cancer of brain, cancer of nerves, cancer of eyes, cancer of meninges, cancer of oropharynx, cancer of hypopharynx, cancer of cervix, and cancer of uterus, glioblastoma, meduloblastoma, astrocytoma, glioma, meningioma, gastrinoma, neuroblastoma, melanoma, myelodysplastic syndrome, a sarcoma, ischemia-reperfusion injury, heart failure, arthritis, rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, Crohn'"'"'s disease, inflammatory bowel disease, ulcerative colitis, lupus, systemic lupus erythematous, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, Grave'"'"'s disease, Hashimoto'"'"'s thyroiditis, Addison'"'"'s disease, celiac disease, dermatomyositis, multiple sclerosis, myasthenia gravis, pernicious anemia, Sjogren syndrome, type I diabetes, vasculitis, uveitis, atherosclerosis, and ankylosing spondylitis.

131. The monoclonal antibody, or antigen binding fragment thereof, of claim 124, wherein the monoclonal antibody, or antigen binding fragment thereof, further exhibits pH-dependent binding to CD47 present on a cell.