IP Library › Granted Patent US 12,661,399
Granted Patent B2
US 12,661,399 · App. 18/012,089 · Granted Jun 23, 2026

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

Inventors: David Berglund (New York, NY); Erik Berglund (New York, NY); Felix Sellberg (Uppsala, SE); Christian Binder (Stockholm, SE)
Assignee: Zelarion Malta Limited
A61K39/3955A61K38/1774A61K47/68A61P37/06C07K14/70521C07K16/2806C07K2317/41C07K2317/52C07K2317/732C07K2317/734C07K2317/76C07K2317/92C07K2319/30
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Quick Facts
Patent No.
US 12,661,399
App. No.
18/012,089
Filed
Dec 21, 2022
Granted
Jun 23, 2026
Kind
B2
Art Unit
1674
USPC
424/133.1
Abstract

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.

Claims (31)

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.

Assignments (4)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 13, 2023
From: BERGLUND, DAVID; BERGLUND, ERIK
To: ITB-MED LLC
Reel/Frame 062960/0313 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 13, 2023
From: SELLBERG, FELIX; BINDER, CHRISTIAN
To: ITB-MED AB
Reel/Frame 062960/0316 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 13, 2023
From: ITB-MED LLC
To: ZELARION MALTA LIMITED
Reel/Frame 062960/0319 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 13, 2023
From: ITB-MED AB
To: ITB-MED LLC
Reel/Frame 062960/0322 →
Continuity (4)
Provisional Application 63182095 · Apr 30, 2021
Provisional Application 63135381 · Jan 8, 2021
Provisional Application 63042844 · Jun 23, 2020
Related Publication 20230365687A1 · Nov 16, 2023
References Cited (98)
US 6692743B1 · Bazin et al. · 2004 [cited by applicant]
US 20020159999A1 · Sykes · 2002 [cited by applicant]
US 20030068320A1 · Dingivan · 2003 [cited by applicant]
US 20130183322A1 · Reisner · 2013 [cited by applicant]
US 20220226329A1 · Kawai · 2022 [cited by applicant]
US 20240270845A1 · Berglund et al. · 2024 [cited by applicant]
US 20240285756A1 · Berglund et al. · 2024 [cited by applicant]
WO WO1998007444 · 1998 [cited by applicant]
WO WO2002069904 · 2002 [cited by applicant]
WO WO2002098370 · 2002 [cited by applicant]
WO WO2004022097 · 2004 [cited by applicant]
WO WO2012032525 · 2012 [cited by applicant]
WO WO2014133729 · 2014 [cited by applicant]
WO WO2019108860 · 2019 [cited by applicant]
WO WO2020227647 · 2020 [cited by applicant]
WO WO2020247872 · 2020 [cited by applicant]
WO WO2021259927 · 2021 [cited by applicant]
WO WO2023036745 · 2023 [cited by applicant]
Adams et al., 2016, “Costimulation Blockade in Autoimmunity and Transplantation: The CD28 Pathway,” Journal of Immunology, 197(6):2045-2050. [cited by applicant]
Andreola et al., 2011, “Mechanisms of donor-specific tolerance in recipients of haploidentical combined bone marrow/kidney transplantation,” American Journal of Transplantation, 11(6):1236-1247. [cited by applicant]
Arduin et al., 2015, “Highly reduced binding to high and low affinity mouse Fc gamma receptors by L234A/L235A and N297A Fc mutations engineered into mouse IgG2a,” Molecular Immunology, 63(2):456-463. [cited by applicant]
Arulanandam et al., 1993, “The CD58 (LFA-3) binding site is a localized and highly charged surface area on the AGFCC′C″ face of the human CD2 adhesion domain,” Proceedings of the National Academy of Sciences (PNAS), 90(… [cited by applicant]
Benvenuto et al., 2018, “New frontiers in immunosuppression,” Journal of Thoracic Disease, 10(5):3141-3155. [cited by applicant]
Bierer and Burakoff, 1989, “T-lymphocyte activation: the biology and function of CD2 and CD4,” Immunological Reviews, 111:267-294. [cited by applicant]
Binder et al., 2020, “CD2 Immunobiology,” Frontiers in Immunology, 11:1090 (14 pages). [cited by applicant]
Binder et al., 2020, “Siplizumab, an Anti-CD2 Monoclonal Antibody, Induces a Unique Set of Immune Modulatory Effects Compared to Alemtuzumab and Rabbit Anti-Thymocyte Globulin In Vitro,” Frontiers in Immunology, 11:5925… [cited by applicant]
Bockenstedt et al., 1988, “The CD2 ligand LFA-3 activates T cells but depends on the expression and function of the antigen receptor,” Journal of Immunology, 141(6):1904-1911. [cited by applicant]
Branco et al., 1999, “Selective deletion of antigen-specific, activated T cells by a humanized MAB to CD2 (MEDI-507) is mediated by NK cells,” Transplantation, 68(10):1588-1596. [cited by applicant]
Chung and Dilling, 2020, “Immunosuppressive strategies in lung transplantation,” Annals of Translational Medicine, 8(6):409 (13 pages). [cited by applicant]
Clark et al., 1988, “Activation of rat T lymphocytes by anti-CD2 monoclonal antibodies,” Journal of Experimental Medicine, 167(6):1861-1872. [cited by applicant]
ClinicalTrials.gov Identifier: NCT04311632, “A Dose Escalation Study in de Novo Renal Transplantation,” 2020 (9 pages). [cited by applicant]
Damschroder et al., 2004, “Analysis of human and primate CD2 molecules by protein sequence and epitope mapping with anti-human CD2 antibodies,” Molecular Immunology, 41(10):985-1000. [cited by applicant]
Davies and Sutton, 2015, “Human IgG4: a structural perspective,” Immunological Reviews, 268(1):139-159. [cited by applicant]
Demetris et al., 2016, “2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology: Introduction of Antibody-Mediated Rejection,” American Journal of Transplantation, 16(10):2816-2835. [cited by applicant]
Einarsdottir et al., 2014, “On the perplexingly low rate of transport of IgG2 across the human placenta,” PLoS One, 9(9):e108319 (9 pages). [cited by applicant]
European Association for the Study of the Liver, 2016, “EASL Clinical Practive Guidelines: Liver transplantation,” Journal of Hepatology, 64(2):433-485. [cited by applicant]
GenBank Accession No. NM_001328609.1, “ [cited by applicant]
GenBank Accession No. NM_001767.5, “ [cited by applicant]
Golay et al., 2003, “Rituximab-mediated antibody-dependent cellular cytotoxicity against neoplastic B cells is stimulated strongly by interleukin-2,” Haematologica, 88(9):1002-1012. [cited by applicant]
Grier et al., 2012, “Human immunodeficiency-causing mutation defines CD16 in spontaneous NK cell cytotoxicity,” Journal of Clinical Investigation, 122(10):3769-3780. [cited by applicant]
Hawthorne et al., 2017, “>12 Month function of genetically modified porcine neonatal islet xenografts in baboons,” XP002805102, Database Em Base, Elsevier Science Publishers, Amsterdam, NL, Database accession No. EM B-6… [cited by applicant]
International Search Report and Written Opinion dated Jan. 10, 2022 for PCT/EP2021/066989 (21 pages). [cited by applicant]
Kellner et al., 2017, “Modulating Cytotoxic Effector Functions by Fc Engineering to Improve Cancer Therapy,” Transfusion Medicine and Hemotherapy, 44(5):327-336. [cited by applicant]
Kinnear et al., 2013, “Costimulation blockade: current perspectives and implications for therapy,” Transplantation, 95(4):527-535. [cited by applicant]
Krummel and Allison, 1995, “CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation,” Journal of Experimental Medicine, 182(2):459-465. [cited by applicant]
Lo et al., 2011, “Selective targeting of human alloresponsive CD8+ effector memory T cells based on CD2 expression,” American Journal of Transplantation, 11(1):22-33. [cited by applicant]
Lo et al., 2011, “Selective targeting of human alloresponsive CD8<+> effector memory T cells based on CD2 expression,” XP002805103, Database Em Base, Elsevier Science Publishers, Amsterdam, NL, Database accession No. EM… [cited by applicant]
Massart et al., 2017, “Operational tolerance in kidney transplantation and associated biomarkers,” Clinical & Experimental Immunology, 189(2):138-157. [cited by applicant]
Newell and Turka, 2015, “Tolerance signatures in transplant recipients,” Current Opinion in Organ Transplantation, 20(4):400-405. [cited by applicant]
Ng et al., 2001, “Human CD4(+)CD25(+) cells: a naturally occurring population of regulatory T cells,” Blood, 98(9):2736-2744. [cited by applicant]
Nizet et al., 1999, “Apoptosis of human naive NK cells mediated by a rat IgG2b anti CD2 mAb through a fractricidal ADCC reaction,” Immunology Letters, 68(2-3):229-235. [cited by applicant]
O'Mahony et al., 2007, “EBV-Related Lymphoproliferative Disease Complicating Therapy with Siplizumab, a Novel Anti-CD2 Mediated T- and NK-Cell Depleting Agent, in Patients with T-Cell Malignancies,” Blood, 110(11):3565 … [cited by applicant]
Orange et al., 2003, “The mature activating natural killer cell immunologic synapse is formed in distinct stages,” Proceedings of the National Academy of Sciences (PNAS), 100(24):14151-14156. [cited by applicant]
Paul and Lal, 2017, “The Molecular Mechanism of Natural Killer Cells Function and Its Importance in Cancer Immunotherapy,” Frontiers in Immunology, 8:1124 (15 pages). [cited by applicant]
Peterson and Seed, 1987, “Monoclonal antibody and ligand binding sites of the T cell erythrocyte receptor (CD2),” Nature, 329(6142):842-846. [cited by applicant]
Podestà et al., 2019, “Siplizumab selectively depletes effector memory T cells and promotes a relative expansion of alloreactive regulatory T cells in vitro,” American Journal of Transplantation, 20(1):88-100. [cited by applicant]
Sambucci et al. 2018, “FoxP3 isoforms and PD-1 expression by T regulatory cells in multiple sclerosis,” Scientific Reports, 8(1):3674 (9 pages). [cited by applicant]
Schlothauer et al., 2016, “Novel human IgG1 and IgG4 Fc-engineered antibodies with completely abolished immune effector functions,” Protein Engineering, Design and Selection, 29(10):457-466. [cited by applicant]
Sellberg et al., 2020, “Pharmacokinetic and pharmacodynamic study of a clinically effective anti-CD2 monoclonal antibody,” Scandinavian Journal of Immunology, 91(1):e12839 (11 pages). [cited by applicant]
Shaffer et al., 2007, “Regulatory T-cell recovery in recipients of haploidentical nonmyeloablative hematopoietic cell transplantation with a humanized anti-CD2 mAb, MEDI-507, with or without fludarabine,” Experimental H… [cited by applicant]
Silva et al., 2015, “The S228P mutation prevents in vivo and in vitro IgG4 Fab-arm exchange as demonstrasted using a combination of novel quantitative immunoassays and physiological matrix preparation,” Journal of Biolo… [cited by applicant]
Sjögren et al., 2013, “EndoS2 is a unique and conserved enzyme of serotype M49 group A [cited by applicant]
Sjögren et al., 2015, “EndoS and EndoS2 hydrolyze Fc-glycans on therapeutic antibodies with different glycoform selectivity and can be used for rapid quantification of high-mannose glycans,” Glycobiology, 25(10):1053-10… [cited by applicant]
Thum et al., 2004, “An increase in the absolute count of CD56dimCD16+CD69+ NK cells in the peripheral blood is associated with a poorer IVF treatment and pregnancy outcome,” Human Reproduction, 19(10):2395-2400. [cited by applicant]
Tradtrantip et al., 2013, “Enzymatic deglycosylation converts pathogenic neuromyelitis optica anti-aquaporin-4 immunoglobulin G into therapeutic antibody,” Annals of Neurology, 73(1):77-85. [cited by applicant]
Valenzuela and Schaub, 2018, “The Biology of IgG Subclasses and Their Clinical Relevance to Transplantation,” Transplantation, 102(Suppl. 1):S7-S13. [cited by applicant]
Van der Mark et al., 2020, “Developments in lung transplantation over the past decade,” European Respiratory Review, 29(157):190132 (16 pages). [cited by applicant]
Van der Merwer et al., 1994, “Human cell-adhesion molecule CD2 binds CD58 (LFA-3) with a very low affinity and an extremely fast dissociation rate but does not bind CD48 or CD59,” Biochemistry, 33(33):10149-10160. [cited by applicant]
Vidarsson et al., 2014, “IgG subclasses and allotypes: from structure to effector functions,” Frontiers in Immunology, 5:520 (17 pages). [cited by applicant]
Walunas et al., 1994, “CTLA-4 can function as a negative regulator of T cell activation,” Immunity, 1(5):405-413. [cited by applicant]
Wang et al.,, 2018, “IgG Fc engineering to modulate antibody effector functions,” Protein Cell, 9(1):63-73. [cited by applicant]
Watzl, C, 2014, “How to trigger a killer: modulation of natural killer cell reactivity on many levels,” Advances in Immunology, 124:137-170. [cited by applicant]
Zhang and Vignali, 2016, “Co-stimulatory and Co-inhibitory Pathways in Autoimmunity,” Immunity, 44(5):1034-1051. [cited by applicant]
International Search Reprot and Written Opinion dated Nov. 30, 2022 for PCT/EP2022/074646 (13 pages). [cited by applicant]
Benjamini et al., 1991, “Immunology: A Short Course,” 2nd edition, p. 40, Wiley-Liss. [cited by applicant]
Bhattacharya et al., 2017, “Impact of genetic variation on three dimensional structure and function of proteins,” PLoS ONE 12(3):e0171355. [cited by applicant]
Brudno et al., 2016, “Toxicities of chimeric antigen receptor T cells: recognition and management,” Blood, 127(26):3321-3330. [cited by applicant]
Chauhan, et al., 2019, “Rituximab in kidney disease and transplant,” Animal Model Exp Med, 2:76-82. [cited by applicant]
ClinicalTrials.gov Identifier: NCT00801632, “Combined Kidney and Bone Marrow Transplantation to Prevent Kidney Transplant Rejection,” 2015 (17 pages). [cited by applicant]
ClinicalTrials.gov Identifier: NCT02108600, “Tocilizumab for Renal Graft Inflammation,” 2021 (14 pages). [cited by applicant]
Dey et al., 2005, “Anti-tumour response despite loss of donor chimaerism in patients treated with non-myeloablative conditioning and allogeneic stem cell transplantation,” British Journal of Haematology, 2005, 128, 351-… [cited by applicant]
Ferrara et al., 2015, “Recombinant renewable polyclonal antibodies,” mAbs, 7(1):32-42. [cited by applicant]
Hay, K., 2018, “Cytokine release syndrome and neurotoxicity after CD19chimeric antigen receptor-modified (CAR-) T cell therapy,” British Journal of Haematology, 183:364-374. [cited by applicant]
Kawai et al, 2014, “Long-Term Results in Recipients of Combined HLA-Mismatched Kidney and Bone Marrow Transplantation Without Maintenance Immunosuppression: Kidney Transplant Without Immunosuppression,” Amerian Journal … [cited by applicant]
Latinne, et al., 1996, “An anti-CD2 mAb induces immunosuppression and hyporesponsiveness of CD2+ human T cells in vitro,” International Immunology, 8(7): 1113-1119. [cited by applicant]
Le et al, 2018, “FDA Approval Summary: Tocilizumab for Treatment of Chimeric Antigen Receptor T Cell-Induced Severe or Life-Threatening Cytokine Release Syndrome,” The Oncologist, 23:943-947. [cited by applicant]
Lee et al, 2020, “Inducing Transient Mixed Chimerism for Allograft Survival Without Maintenance Immunosuppression With Combined Kidney and Bone Marrow Transplantation: Protocol Optimization,” 104(7):1472-1482. [cited by applicant]
LoCasico et al., 2010, “Mixed Chimerism, Lymphocyte Recovery, and Evidence for Early Donor-Specific Unresponsiveness in Patients Receiving Combined Kidney and Bone Marrow Transplantation to Induce Tolerance,” Transplant… [cited by applicant]
Lowsky et al., 2022, “Establishment of Chimerisn and Organ Transplant Tolerance in Laboratory Animals: Safety and Efficacy of Adaptation to Humans,” Frontiers in Immunology, vol. 13. [cited by applicant]
Nizet et al., 2000, “The Experimental (In Vitro) and Clinical (In Vivo) Immunosuppressive Effects of a Rat IgG2b Anti-Human CD2 mAb, LO-CD2a/BTI-322,” Transplantation, 69(7):1420-1429. [cited by applicant]
Podestà et al., 2022, “Chimerism-Based Tolerance to Kidney Allografts in Humans: Novel Insights and Future Perspectives,” Frontiers in Immunology, vol. 12. [cited by applicant]
Sasaki et al, 2018, “Preclinical and clinical studies for transplant tolerance via the mixed chimerism approach,” Human Immunology, 79(5):258-265. [cited by applicant]
Savage et al. 2018, “Early expansion of donor-specific Tregs in tolerant kidney transplant recipients,” JCI Insight., 3(22): e124086. doi: 10.1172/jci.insight.124086. [cited by applicant]
Schinnerling et al, 2017, “The role of interleukin-6 signalling and its therapeutic blockage in skewing the T cell balance in rheumatoid arthritis,” Clinical and Experimental Immunology, 189(1):12-20. [cited by applicant]
Sprangers et al., 2017, “Origin of Enriched regulatory t cells in patients receiving combined kidney/bone marrow transplantation to induce transplantation tolerance,” Am J Transplant. 17(8): 2020-2032. doi: 10.1111/ajt.… [cited by applicant]
Tada et al., 2016, “The balance between Foxp3 and Ror-γt expression in peripheral blood is altered by tocilizumab and abatacept in patients with rheumatoid arthritis,” BMC Musculoskeletal Disorders, 17:290. [cited by applicant]
Tokuriki et al., 2009, “Stability effects of mutations and protein evolvability,” Current Opinion in Structural Biology, 19:596-604. [cited by applicant]
Xu et al., 2004, “The anti-CD2 monoclonal antibody BTI-322 generates unresponsiveness by activation-associated T cell depletion,” Clinical and Experimental Immunology, 138(3):476-483. [cited by applicant]