Anti-cd117 antibody-drug conjugates and uses thereof
OwnerCharlotte F. McDonagh, Anthony Boitano +3inventors
InventorsCharlotte F. McDonagh, Anthony Boitano, Michael Cooke, Ganapathy N. Sarma, Rajiv Panwar
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Abstract
Anti-CD117 antibody-drug conjugates (ADCs) comprising pyrrolobenzodiazepine are provided, as well as compositions and methods of using the same. The compositions and methods provided herein can also be used to prepare a patient for hematopoietic stem cell transplant therapy and to improve the engraftment of hematopoietic stem cell transplants by selectively depleting endogenous hematopoietic stem cells prior to the transplant procedure. Methods and compositions for the treatment of various hematopoietic diseases, metabolic disorders, cancers, and autoimmune diseases, are provided.
Claims38
An antibody-drug conjugate (ADC) comprising an anti-CD117 antibody, or antigen binding portion thereof (Ab), conjugated to a cytotoxin (Cy) via a linker (L), wherein the cytotoxin comprises a pyrrolobenzodiaze pine (PBD), wherein the antibody, or the antigen binding fragment thereof, wherein anti-CD117 antibody, or antigen binding portion thereof, comprises
- a heavy chain comprising a heavy chain (HC)-CDR1, HC-CDR2, and HC-CDR3 comprising an amino acid sequence as set forth in SEQ ID No:
- 11, 12, and 13, respectively, and a light chain comprising a light chain (LC)-CDR1, LC-CDR2, and LC-CDR3 comprising an amino acid sequence as set forth in SEQ ID Nos:
- 14, 15, and 16, respectively;
- a heavy chain comprising a heavy chain (HC)-CDR1, HC-CDR2, and HC-CDR3 comprising an amino acid sequence as set forth in SEQ ID Nos:
- 245, 246, and 247, respectively, and a light chain comprising a light chain (LC)-CDR1, LC-CDR2, and LC-CDR3 comprising an amino acid sequence as set forth in SEQ ID Nos:
- 248, 249, and 250, respectively;
- or
- a heavy chain comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 or a variable region from the heavy chain variable region amino acid sequence of SEQ ID NO:
- 147, 164, 166, 168, 170, 172, 174, 176, 178, 180, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, or 238, and a light chain comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 or a variable region from the light chain variable region amino acid sequence of SEQ ID NO:
- 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 203, 205, 207, 209, 211, 213, 215, 217, 219, 221, 223, 225, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 239, 240, 241, or 242.
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-17. (canceled)
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A method of depleting a population of CD117+ cells in a human patient in need of a hematopoietic stem cell transplant, the method comprising administering to the human patient an effective amount of an antibody-drug conjugate (ADC) comprising a pyrrolobenzodiazepine (PBD) conjugated to an antibody or antigen binding portion thereof capable of specifically binding human CD117, wherein the antibody or antigen binding portion thereof comprises an Fc domain and is internalized by a CD117+ cell, and wherein the antibody comprises
- a heavy chain comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 or a variable region from the heavy chain variable region amino acid sequence of SEQ ID NO:
- 147, 164, 166, 168, 170, 172, 174, 176, 178, 180, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 238, or 243, and a light chain comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 or a variable region from the light chain variable region amino acid sequence of SEQ ID NO:
- 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 203, 205, 207, 209, 211, 213, 215, 217, 219, 221, 223, 225, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 239, 240, 241, 242, or 244;
- a heavy chain comprising a variable region comprising an amino acid sequence as set forth in SEQ ID NO:
- 9 and a light chain comprising a variable region comprising an amino acid sequence as set forth in SEQ ID NO:
- 10;
- or
- a heavy chain comprising a variable region comprising an amino acid sequence as set forth in SEQ ID NO:
- 243, and a light chain comprising a variable region comprising an amino acid sequence as set forth in SEQ ID NO:
- 244.
A method of conditioning a human patient for receiving a hematopoietic stem cell (HSC) transplant, the method comprising administering to the human patient an effective amount of an antibody-drug conjugate (ADC) comprising a pyrrolobenzodiazepine (PBD) conjugated to an antibody or antigen binding portion thereof capable of specifically binding human CD117, wherein the antibody or antigen binding portion thereof, comprises an Fc domain and is internalized by a CD117+ cell, and wherein the human patient has a stem cell disorder, and wherein the antibody comprises
- a heavy chain comprising an HC-CDR1, an HC-CDR2, and an HC-CDR3 or a variable region from the heavy chain variable region amino acid sequence of SEQ ID NO:
- 147, 164, 166, 168, 170, 172, 174, 176, 178, 180, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222, 224, 226, 238, or 243, and a light chain comprising an LC-CDR1, an LC-CDR2, and an LC-CDR3 or a variable region from the light chain variable region amino acid sequence of SEQ ID NO:
- 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 203, 205, 207, 209, 211, 213, 215, 217, 219, 221, 223, 225, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 239, 240, 241, 242, or 244;
- a heavy chain comprising a variable region comprising an amino acid sequence as set forth in SEQ ID NO:
- 9 and a light chain comprising a variable region comprising an amino acid sequence as set forth in SEQ ID NO:
- 10;
- or
- a heavy chain comprising a variable region comprising an amino acid sequence as set forth in SEQ ID NO:
- 243, and a light chain comprising a variable region comprising an amino acid sequence as set forth in SEQ ID NO:
- 244.
Dependencies are inferred from the claim text.