Methods of use of anti-CD45 antibodies and conjugates thereof
Disclosed are anti-CD45 antibodies, antigen binding fragments thereof, and antibody drug conjugates (ADCs) that specifically bind to human CD45. Such antibodies and ADCs are useful in therapeutic methods, including methods of depleting CD45+ cells from a patient. The compositions and methods described herein can be used to treat a disorder directly, for instance, by depleting a population of CD45+ cancer cells or autoimmune cells. The compositions and methods described 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 CD45+ cells prior to the transplant procedure.
1 . A method of depleting a population of CD45+ cells in a human patient in need thereof, the method comprising administering to the patient an effective amount of an antibody drug conjugate (ADC);
wherein the human patient has a hematological cancer and is in need of a hematopoietic stem cell transplant,
wherein the ADC comprises an anti-CD45 antibody, or an antigen-binding portion thereof, conjugated to a cytotoxin via a linker, wherein the cytotoxin is a DNA alkylating agent, and
wherein the anti-CD45 antibody, or antigen-binding portion thereof comprises a heavy chain comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 42, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:43, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO:44; and a light chain comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 46, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:47; and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO:48.
2 . The method of claim 1 , wherein
the CD45+ cells are depleted from the bone marrow of the patient and/or from the peripheral blood of the patient.
3 . The method of claim 1 , further comprising administering to the patient a transplant comprising hematopoietic stem cells.
4 . A method of treating a human patient having a hematological cancer, the method comprising
(a) administering to a human patient an antibody drug conjugate (ADC), in an amount sufficient to deplete a population of CD45+ cells in the patient, wherein the human patient has a hematological cancer; and
(b) subsequently administering to the patient a transplant comprising hematopoietic stem cells,
wherein the ADC comprises an anti-CD45 antibody, or an antigen-binding portion thereof, conjugated to a cytotoxin via a linker, wherein the cytotoxin is a DNA alkylating agent, and
wherein the anti-CD45 antibody, or antigen-binding portion thereof comprises a heavy chain comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 42, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:43, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO:44; and a light chain comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 46, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:47; and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO:48.
5 . The method of claim 4 ,
wherein the transplant is allogeneic or autologous; or
wherein the transplant comprising hematopoietic stem cells is administered to the patient after the concentration of the ADC has substantially cleared from the blood of the patient.
6 . The method of claim 1 , wherein the hematological cancer is acute myeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia, chronic lymphoid leukemia, or multiple myeloma.
7 . The method of claim 1 , wherein the heavy chain comprises a variable region comprising an amino acid sequence as set forth in SEQ ID NO: 41, and wherein the light chain comprises a variable region comprising an amino acid sequence as set forth in SEQ ID NO: 45.
8 . The method of claim 1 , wherein the heavy chain comprises an amino acid sequence as set forth in SEQ ID NO: 49, and the light chain comprises an amino acid sequence as set forth in SEQ ID NO: 50.
9 . The method of claim 1 , wherein the heavy chain comprises an amino acid sequence as set forth in SEQ ID NO: 106, and the light chain comprises an amino acid sequence as set forth in SEQ ID NO: 101.
10 . The method of claim 1 , wherein the cytotoxin is an indolinobenzodiazepine or an indolinobenzodiazepine pseudodimer.
11 . The method of claim 1 , wherein the cytotoxin has a structure represented by:
wherein the wavy line indicates the point of covalent attachment to the linker of the ADC.
12 . The method of claim 4 , wherein the heavy chain comprises a variable region comprising an amino acid sequence as set forth in SEQ ID NO: 41, and wherein the light chain comprises a variable region comprising an amino acid sequence as set forth in SEQ ID NO: 45.
13 . The method of claim 4 , wherein the heavy chain comprises an amino acid sequence as set forth in SEQ ID NO: 49, and the light chain comprises an amino acid sequence as set forth in SEQ ID NO: 50.
14 . The method of claim 4 , wherein the heavy chain comprises an amino acid sequence as set forth in SEQ ID NO: 106, and the light chain comprises an amino acid sequence as set forth in SEQ ID NO: 101.
15 . The method of claim 4 , wherein the cytotoxin is an indolinobenzodiazepine or an indolinobenzodiazepine pseudodimer.
16 . The method of claim 4 , wherein the cytotoxin has a structure represented by:
wherein the wavy line indicates the point of covalent attachment to the linker of the ADC.
17 . A method of depleting a population of CD45+ cells in a human patient in need thereof, the method comprising administering to the patient an effective amount of an antibody drug conjugate (ADC),
wherein the human patient has acute myeloid leukemia (AML) and is in need of a hematopoietic stem cell transplant,
wherein the ADC comprises an anti-CD45 antibody, or an antigen-binding portion thereof, conjugated to a DNA alkylating agent via a linker, and
wherein the anti-CD45 antibody, or antigen-binding portion thereof, comprises a heavy chain comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 42, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:43, and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO:44; and a light chain comprising a CDR1 domain comprising the amino acid sequence as set forth in SEQ ID NO: 46, a CDR2 domain comprising the amino acid sequence as set forth in SEQ ID NO:47; and a CDR3 domain comprising the amino acid sequence as set forth in SEQ ID NO:48.
18 . The method of claim 17 , wherein the heavy chain comprises a variable region comprising an amino acid sequence as set forth in SEQ ID NO: 41, and wherein the light chain comprises a variable region comprising an amino acid sequence as set forth in SEQ ID NO: 45.
19 . The method of claim 17 , wherein the heavy chain comprises an amino acid sequence as set forth in SEQ ID NO: 49, and the light chain comprises an amino acid sequence as set forth in SEQ ID NO: 50.
20 . The method of claim 17 , wherein the heavy chain comprises an amino acid sequence as set forth in SEQ ID NO: 106, and the light chain comprises an amino acid sequence as set forth in SEQ ID NO: 101.
21 . The method of claim 17 , further comprising administering to the patient a transplant comprising hematopoietic stem cells.