Anti-CD45 antibody drug conjugates and uses thereof
The invention provides anti-CD45 antibody drug conjugates (ADCs), and methods of use thereof. In one embodiment, the invention provides methods of depleting a population of CD45+ cells from a subject, by administration of an anti-CD45 ADC provided herein. In some embodiments, the ADCs include a cytotoxin containing a benzodiazepine moiety, for example. a pyrrolobenzodiazepine (PBD) or an indolinobenzodiazepine (IGN) moiety.
1 . A method of depleting a population of CD45+ cells in a human patient in need of a hematopoietic stem cell (HSC) transplant, the method comprising administering to the human patient an effective amount of an antibody-drug conjugate (ADC), such that a population of CD45+ cells are depleted, wherein the ADC comprises an anti-CD45 antibody or antigen binding portion thereof conjugated to a cytotoxin (Cy) via a linker (L), wherein the cytotoxin comprises an indolinobenzodiazepine (IGN) pseudodimer, and wherein the anti-CD45 antibody is an IgG isotype,
wherein the cytotoxin-linker conjugate, prior to conjugation to the antibody or antigen binding portion thereof, and including the reactive substituent Z′, taken together as Cy-L-Z′, wherein the linker has a structure of formula:
(VII).
2 . The method of claim 1 , wherein the cytotoxin is an IGN pseudodimer represented by Formula (VI):
wherein the wavy line indicates the point of covalent attachment to the linker of the ADC.
3 . The ADC of claim 1 , wherein the cytotoxin is an IGN and the cytotoxin-linker conjugate, prior to conjugation to the antibody or antigen binding portion thereof, and including the reactive substituent Z′, taken together as Cy-L-Z′, has a structure of Formula (VII):
4 . The method of claim 1 , wherein the antibody is a chimeric antibody, a humanized antibody, or a human antibody.
5 . The method of claim 1 , wherein the antibody or antigen binding portion thereof comprises an Fc domain and is internalized by a CD45+ cell and/or wherein the antibody, or antigen binding portion thereof, is conjugated to the cytotoxin by way of a cysteine residue in the Fc domain.
6 . The method of claim 1 , wherein the method further comprising administering a hematopoietic stem cell transplant to the patient, or comprises administering the ADC to the patient prior to the patient receiving a transplant comprising hematopoietic stem cells.
7 . The method of claim 1 , wherein the patient has a blood disease, a metabolic disorder, a cancer, an autoimmune disease, a stem cell disorder, or severe combined immunodeficiency disease (SCID).
8 . The method of claim 7 , wherein the autoimmune disease is multiple sclerosis or scleroderma.
9 . The method of claim 7 , wherein the cancer is a hematological cancer.
10 . The method of claim 9 , wherein the hematological cancer is leukemia or lymphoma.
11 . The method of claim 1 , wherein a population of endogenous CD45+ HSCs are depleted in the human patient following administration of the ADC.
12 . A method of conditioning a human patient for receiving a hematopoietic stem cell (HSC) transplant, the method comprising administering to the human patient an antibody-drug conjugate (ADC), wherein the ADC comprises an anti-CD45 antibody or antigen binding portion thereof conjugated to a cytotoxin (Cy) via a linker (L), wherein the cytotoxin comprises an indolinobenzodiazepine (IGN) pseudodimer, and wherein the anti-CD45 antibody is an IgG isotype,
wherein the cytotoxin-linker conjugate, prior to conjugation to the antibody or antigen binding portion thereof, and including the reactive substituent Z′, taken together as Cy-L-Z′
wherein the linker has a structure of formula: