T-CELL DEPLETING THERAPIES
Provided herein are methods of depleting T cells for therapeutic uses, including administration of anti-CD2 or anti-CD5 antibody drugs conjugates (ADCs) for treatment. Provided are anti-CD2 ADCs or anti-CD5 ADCs for use as agents to treat a stem cell disorder, cancer, or autoimmune disease, among other hematological and proliferative diseases. The compositions and methods described can be used to deplete populations of CD2+ or CD5+ cells, such as CD2+ or CD5+ cancer cells or CD2+ or CD5+ immune cells, and can also be used to prepare a patient for hematopoietic stem cell transplantation or solid organ transplantation.
1 . A method of depleting T cells in a subject having an autoimmune disease, said method comprising administering an effective amount of either an anti-CD5 antibody drug conjugate (ADC) or an anti-CD2 ADC to a subject having an autoimmune disease, wherein the ADC comprises an anti-CD5 antibody, or antigen-binding fragment thereof, or an anti-CD2 antibody, or antigen-binding fragment thereof, conjugated to a cytotoxin via a linker.
2 . The method of claim 1 , wherein the effective amount is an amount sufficient to substantially deplete endogenous CD5+ or CD2+ T cells in the thymus of the subject.
3 . The method of claim 1 , wherein the subject has multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus (SLE), or systemic sclerosis (SSc).
4 . A method of treating a subject having steroid-refractory graft versus host disease (GVHD) or at risk for developing GVHD, said method comprising administering an anti-CD2 ADC or an anti-CD5 ADC to the subject having steroid-refractory GVHD, such that the steroid refractory GVHD is treated, wherein the ADC comprises an anti-CD5 antibody, or antigen-binding fragment thereof, or an anti-CD2 antibody, or antigen-binding fragment thereof, conjugated to a cytotoxin via a linker.
5 . The method of claim 4 , wherein the steroid refractory GVHD is steroid refractory acute GVHD.
6 . The method of claim 4 , wherein the subject previously received an allogeneic HSC transplant.
7 . The method of claim 5 , wherein the subject has steroid refractory acute GVHD Grade 2 to Grade 4 (Mount Sinai acute GVHD International Consortium (MAGIC) criteria).
8 . The method of claim 7 , wherein the GVHD grade is decreased by one grade according to the MAGIC criteria following administration of the anti-CD2 ADC or anti-CD5 ADC.
9 . A method of treating a subject having a T cell malignancy, said method comprising administering an effective amount of an anti-CD2 ADC or an anti-CD5 ADC to the subject, wherein the ADC comprises an anti-CD5 antibody, or antigen-binding fragment thereof, or an anti-CD2 antibody, or antigen-binding fragment thereof, conjugated to a cytotoxin via a linker.
10 . (canceled)
11 . The method of claim 9 , wherein the T cell malignancy is a lymphoma, a T-cell acute lymphoblastic lymphoma (T-ALL), T-cell large granular lymphocyte (LGL) leukemia, human T-cell leukemia virus type 1-positive (HTLV-1+), adult T-cell leukemia/lymphoma (ATL), T-cell prolymphocytic leukemia (T-PLL), or peripheral T-cell lymphoma (PTCLs).
12 . The method of claim 10 , wherein in the T cell malignancy is a relapsed, refractory T cell malignancy.
13 . (canceled)
14 . The method of claim 1 , wherein the antibody has an isotype selected from the group consisting of IgG, IgA, IgM, IgD, and IgE.
15 . (canceled)
16 . The method of claim 1 , wherein the ADC is an anti-CD5 ADC or an anti-CD2 ADC.
17 . (canceled)
18 . The method of claim 1 , wherein the cytotoxin is selected from the group consisting of pseudomonas exotoxin A, deBouganin, diphtheria toxin, an amatoxin, saporin, maytansine, a maytansinoid, an auristatin, an anthracycline, a calicheamicin, irinotecan, SN-38, a duocarmycin, a pyrrolobenzodiazepine, a pyrrolobenzodiazepine dimer, an indolinobenzodiazepine, or an indolinobenzodiazepine dimer.
19 . The method of claim 1 , wherein the cytotoxin is an RNA polymerase inhibitor.
20 . The method of claim 19 , wherein the RNA polymerase inhibitor is an RNA polymerase II inhibitor.
21 . The method of claim 19 , wherein the RNA polymerase inhibitor is an amatoxin.
22 . The method of claim 1 , wherein the ADC is represented by the formula Ab-Z-L-Am, wherein Ab is the anti-CD5 antibody or antigen-binding fragment thereof, L is a linker, Z is a chemical moiety, and Am an amatoxin represented by formula (I)
wherein R 1 is H, OH, OR A , or OR C ;
R 2 is H, OH, OR B , or OR C ;
R A and R B , when present, together with the oxygen atoms to which they are bound, combine to form an optionally substituted 5-membered heterocyclolalkyl group;
R 3 is H, R C , or R D ;
R 4 , R 5 , R 6 , and R 7 are each independently H, OH, OR C , OR D , R C , or R D ;
R 8 is OH, NH 2 , OR C , OR D , NHR C , or NR C R D ;
R 9 is H, OH, OR C , or OR D ;
X is —S—, —S(O)—, or —SO 2 —;
R C is -L-Z;
R D is optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 heteroalkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 2 -C 6 heteroalkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
L is optionally substituted C 1 -C 6 alkylene, optionally substituted C 1 -C 6 heteroalkylene, optionally substituted C 2 -C 6 alkenylene, optionally substituted C 2 -C 6 heteroalkenylene, optionally substituted C 2 -C 6 alkynylene, optionally substituted C 2 -C 6 heteroalkynylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene, optionally substituted arylene, optionally substituted heteroarylene, a dipeptide, —C(═O)—, a peptide. or a combination thereof; and
Z is a chemical moiety formed from a coupling reaction between a reactive substituent present on L and a reactive substituent present within the antibody or antigen-binding fragment thereof,
wherein Am comprises exactly one R C substituent.
23 - 24 . (canceled)
25 . The method of claim 1 , wherein the ADC is represented by the formula Ab-Z-L-Am, wherein Ab is the antibody or antigen-binding fragment thereof, Z is a chemical moiety, L is a linker, and Am is an amatoxin, and the amatoxin-linker conjugate Am-L-Z is represented by formula (II), formula (IIA), or formula (IIB)
wherein X is S, SO, or SO 2 ;
R 1 is H or a linker covalently bound to the antibody or antigen-binding fragment thereof through a chemical moiety Z, formed from a coupling reaction between a reactive substituent present on the linker and a reactive substituent present within an antibody, or antigen-binding fragment thereof; and
R 2 is H or a linker covalently bound to the antibody or antigen-binding fragment thereof through a chemical moiety Z, formed from a coupling reaction between a reactive substituent present on the linker and a reactive substituent present within an antibody, or antigen-binding fragment thereof;
wherein when R 1 is H, R 2 is the linker, and when R 2 is H, R 1 is the linker.
26 . The method of claim 1 , wherein the cytotoxin of the ADC is which is a maytansinoid, an auristatin, or an anthracycline.
27 . The method of claim 26 , wherein the maytansinoid is DM1 or DM4.
28 - 30 . (canceled)
31 . The method of claim 26 , wherein the anthracycline is daunorubicin, doxorubicin, epirubicin, or idarubicin.
32 . The method of claim 1 , wherein the cytotoxin of the ADC is a pyrrolobenzodiazepine dimer derivative represented by formula (IV)
33 . The method of claim 1 , wherein the ADC is internalized by a CD5+ or a CD2+ immune cell following administration to the patient.
34 - 35 . (canceled)
36 . The method of claim 33 , wherein the immune cell is a malignant T cell.
37 . The method of claim 1 , wherein the subject is a human.
38 . The method of claim 1 , wherein:
the anti-CD5 antibody, or antigen-binding portion thereof, comprises a heavy chain comprising a variable region as set forth in the amino acid sequence of SEQ ID NO: 282, and a light chain comprising a variable region comprising the amino acid sequence set forth in SEQ ID NO: 283;
the anti-CD5 antibody, or antigen-binding portion thereof, comprises a heavy chain comprising a variable region as set forth in the amino acid sequence of SEQ ID NO: 288, and a light chain comprising a variable region comprising the amino acid sequence set forth in SEQ ID NO: 289; or
the anti-CD5 antibody, or antigen-binding portion thereof, comprises a heavy chain comprising a variable region as set forth in the amino acid sequence of SEQ ID NO: 291, and a light chain comprising a variable region comprising the amino acid sequence set forth in SEQ ID NO: 290.
39 - 40 . (canceled)