Method of treating an immune-related disorder or disease associated with an organ or tissue transplant with a combination of an anti-CD2 antibody and a CTLA-4 co-stimulation blockade
Provided herein are improved anti-CD2 antibodies and methods for their use in the treatment and/or prevention of chronic or acute disorders of the immune system. Also provided herein are methods for treating or preventing an immune related disorder or disease in a subject by administering an anti-CD2 antibody or an antigen-binding fragment thereof and a CTLA-4 co-stimulation blockade. Compositions for use with these methods and kits are also disclosed.
1 . A method of treating or preventing an immune-related disorder or disease associated with a kidney transplant or a transplant of kidney tissue in a subject in need thereof, the method comprising:
a) administering more than one dose of an anti-CD2 antibody or an antigen-binding fragment thereof to the subject; and
b) administering a CTLA-4 co-stimulation blockade to the subject, wherein the CTLA-4 co-stimulation blockade comprises the amino acid sequence of SEQ ID NO: 22:
wherein a dose of about or at least about 0.6 mg/kg of the anti-CD2 antibody or antigen-binding fragment thereof is administered to the subject on the same day that the kidney or tissue thereof is transplanted into the subject, and wherein another dose of the anti-CD2 antibody or antigen-binding fragment thereof is administered to the subject once within two weeks after the kidney or tissue thereof is transplanted into the subject; and wherein the anti-CD2 antibody or antigen-binding fragment thereof comprises:
i) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 3;
ii) a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 4;
iii) a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 5;
iv) a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 6;
v) a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 7; and
vi) a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 8.
2 . The method of claim 1 , wherein the CTLA-4 co-stimulation blockade is belatacept.
3 . The method of claim 1 , wherein the immune-related disorder or disease is a disease associated with the kidney transplant or transplant of kidney tissue, graft rejection, graft-versus-host-disease, or any combination thereof.
4 . The method of claim 1 , wherein a dose of the anti-CD2 antibody or antigen-binding fragment thereof is not therapeutically effective when the CTLA-4 co-stimulation blockade is not administered to the subject.
5 . The method of claim 1 , wherein a dose of the CTLA-4 co-stimulation blockade is not therapeutically effective when the anti-CD2 antibody or antigen-binding fragment thereof is not administered to the subject.
6 . The method of claim 1 , wherein the method results in a greater decrease in the level of CD2 in a biological sample obtained from the subject after both the anti-CD2 antibody or antigen-binding fragment thereof and the CTLA-4 co-stimulation blockade are administered to the subject as compared to:
(a) a decrease in the level of CD2 in a biological sample obtained from the subject prior to at least one of the administering the anti-CD2 antibody or antigen-binding fragment thereof and/or the administering the CTLA-4 co-stimulation blockade to the subject; and/or
(b) a decrease in the level of CD2 in a biological sample obtained from the subject after the anti-CD2 antibody or antigen-binding fragment thereof or after the CTLA-4 co-stimulation blockade, but not both, is administered to the subject; and
wherein the greater decrease is greater by about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 100%, or more than 100%.
7 . The method of claim 1 , wherein the anti-CD2 antibody or antigen-binding fragment thereof is administered to the subject on the day of the kidney or the kidney tissue transplantation, on day 1 after the kidney or the kidney tissue transplantation, and/or on day 4 after the kidney or the kidney tissue transplantation.
8 . The method of claim 1 , wherein the anti-CD2 antibody or antigen-binding fragment thereof is administered intravenously or subcutaneously to the subject.
9 . The method of claim 1 , wherein the method further comprises administering an additional agent to the subject.
10 . The method of claim 9 , wherein the additional agent comprises one or more of a steroid, a calcineurin inhibitor, a cyclosporine, a cyclophosphamide, an antimetabolite therapy, a nonsteroidal anti-inflammatory drugs (NSAID), an agent used for treating rheumatoid arthritis, and/or an mTOR inhibitor.
11 . The method of claim 9 , wherein the additional agent comprises basiliximab induction, mycophenolate mofetil, corticosteroids, or a combination thereof.
12 . The method of claim 1 , wherein a first dose of the anti-CD2 antibody or antigen-binding fragment thereof is administered before a first dose of the CTLA-4 co-stimulation blockade.
13 . The method of claim 1 , wherein a first dose of the anti-CD2 antibody or antigen-binding fragment thereof is administered after a first dose of the CTLA-4 co-stimulation blockade.
14 . The method of claim 1 , wherein a first dose of the anti-CD2 antibody or antigen-binding fragment thereof is administered concurrently with a first dose of the CTLA-4 co-stimulation blockade.
15 . The method of claim 1 , wherein the subject is a treatment-naïve subject.
16 . The method of claim 1 , wherein the subject is resistant to a treatment of the immune-related disorder or disease.
17 . The method of claim 1 , wherein the administering of the anti-CD2 antibody or antigen-binding fragment thereof and the CTLA-4 co-stimulation blockade is synergistic in comparison to the administering the anti-CD2 antibody or to the administering the CTLA-4 co-stimulation blockade, but not both, to the subject.
18 . The method of claim 1 , wherein the administering of the anti-CD2 antibody or antigen-binding fragment thereof and the CTLA-4 co-stimulation blockade results in a greater decrease in alloimmune response in the subject in comparison to a decrease in alloimmune response after the administering the anti-CD2 antibody or the administering the CTLA-4 co-stimulation blockade, but not both, to the subject; and wherein the greater decrease is greater by about or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 100%, or more than 100%.
19 . The method of claim 18 , wherein the alloimmune response is determined using an in vitro human T cell proliferation assay or a mixed lymphocyte reaction (MLR) assay.