Abstract
T cell lymphomas (TCL) are heterogeneous, aggressive, and have few available targeted therapeutics. In this study, we determined that CD6, an established T cell marker, was expressed at high levels on almost all examined TCL patient specimens, suggesting that CD6 could be a new therapeutic target for this life-threatening blood cancer. We prepared a CD6-targeted antibody-drug conjugate (CD6-ADC) by conjugating monomethyl auristatin E (MMAE), an FDA-approved mitotic toxin, to a high-affinity anti-human CD6 monoclonal antibody (mAb). In contrast to both the unconjugated anti-CD6 mAb, and the non-binding control ADC, CD6-ADC potently and selectively killed TCL cells in vitro in both time- and concentration-dependent manners. It also prevented the development of tumors in vivo in a preclinical model of TCL. More importantly, systemic or local administration of the CD6-ADC or its humanized version, but not the controls, significantly shrank established tumors in the preclinical mouse model of TCL. These results suggest that CD6 is a novel therapeutic target in TCLs and provide a strong rationale for the further development of CD6-ADC as a promising therapy for patients with these potentially fatal lymphoid neoplasms.
Similar content being viewed by others
References
Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin. 2021;71:7–33.
Vose J, Armitage J, Weisenburger D, International TCLP. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol. 2008;26:4124–30.
Ma H, Davarifar A, Amengual JE. The Future of Combination Therapies for Peripheral T Cell Lymphoma (PTCL). Curr Hematologic Malignancy Rep. 2018;13:13–24.
Drago JZ, Modi S, Chandarlapaty S. Unlocking the potential of antibody-drug conjugates for cancer therapy. Nat Rev Clin Oncol. 2021;18:327–44.
Francisco JA, Cerveny CG, Meyer DL, Mixan BJ, Klussman K, Chace DF, et al. cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood. 2003;102:1458–65.
Richardson NC, Kasamon YL, Chen H, de Claro RA, Ye J, Blumenthal GM, et al. FDA Approval Summary: Brentuximab Vedotin in First-Line Treatment of Peripheral T-Cell Lymphoma. Oncologist. 2019;24:e180–7.
Kamoun M, Kadin ME, Martin PJ, Nettleton J, Hansen JA. A novel human T cell antigen preferentially expressed on mature T cells and shared by both well and poorly differentiated B cell leukemias and lymphomas. J Immunol. 1981;127:987–91.
Ramos-Casals M, Font J, Garcia-Carrasco M, Calvo J, Places L, Padilla O, et al. High circulating levels of soluble scavenger receptors (sCD5 and sCD6) in patients with primary Sjogren’s syndrome. Rheumatol (Oxf). 2001;40:1056–9.
Braun M, Muller B, ter Meer D, Raffegerst S, Simm B, Wilde S, et al. The CD6 scavenger receptor is differentially expressed on a CD56 natural killer cell subpopulation and contributes to natural killer-derived cytokine and chemokine secretion. J Innate Immun. 2011;3:420–34.
Li Y, Ruth JH, Rasmussen SM, Athukorala KS, Weber DP, Amin MA, et al. Attenuation of Murine Collagen-Induced Arthritis by Targeting CD6. Arthritis Rheumatol. 2020;72:1505–13.
Zhang L, Li Y, Qiu W, Bell BA, Dvorina N, Baldwin WM 3rd, et al. Targeting CD6 for the treatment of experimental autoimmune uveitis. J Autoimmun. 2018;90:84–93.
Li Y, Singer NG, Whitbred J, Bowen MA, Fox DA, Lin F. CD6 as a potential target for treating multiple sclerosis. Proc Natl Acad Sci USA. 2017;114:2687–92.
Dogra S, Uprety S, Suresh SH. Itolizumab, a novel anti-CD6 monoclonal antibody: a safe and efficacious biologic agent for management of psoriasis. Expert Opin Biol Ther. 2017;17:395–402.
Parthasaradhi A. Safety and Efficacy of Itolizumab in the Treatment of Psoriasis: A Case Series of 20 Patients. J Clin Diagn Res. 2016;10:WD01–3.
Dogra S, Shabeer D, Rajagopalan M. Anti-CD6 mAbs for the treatment of psoriasis. Expert Opin Biol Ther. 2020;20:1215–22.
Hsi ED, Said J, Macon WR, Rodig SJ, Ondrejka SL, Gascoyne RD, et al. Diagnostic accuracy of a defined immunophenotypic and molecular genetic approach for peripheral T/NK-cell lymphomas. A North American PTCL study group project. Am J Surg Pathol. 2014;38:768–75.
Garcia Santana CA, Tung JW, Gulnik S. Human treg cells are characterized by low/negative CD6 expression. Cytom A. 2014;85:901–8.
Townsend EC, Murakami MA, Christodoulou A, Christie AL, Koster J, DeSouza TA, et al. The Public Repository of Xenografts Enables Discovery and Randomized Phase II-like Trials in Mice. Cancer Cell. 2016;30:183.
Gill RPK, Gantchev J, Martinez Villarreal A, Ramchatesingh B, Netchiporouk E, Akilov OE, et al. Understanding Cell Lines, Patient-Derived Xenograft and Genetically Engineered Mouse Models Used to Study Cutaneous T-Cell Lymphoma. Cells. 2022;11:593.
Fiore D, Cappelli LV, Broccoli A, Zinzani PL, Chan WC, Inghirami G. Peripheral T cell lymphomas: from the bench to the clinic. Nat Rev Cancer. 2020;20:323–42.
Horwitz S, O’Connor OA, Pro B, Trumper L, Iyer S, Advani R, et al. The ECHELON-2 Trial: 5-year results of a randomized, phase III study of brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma. Ann Oncol. 2022;33:288–98.
Cattoretti G. MYC expression and distribution in normal mature lymphoid cells. J Pathol. 2013;229:430–40.
Alzona M, Jack HM, Fisher RI, Ellis TM. CD30 defines a subset of activated human T cells that produce IFN-gamma and IL-5 and exhibit enhanced B cell helper activity. J Immunol. 1994;153:2861–7.
Acknowledgements
This project was supported in part by a Velosano pilot grant from Cleveland Clinic (FL) and NIH grants EY025373, EY033243 and CA275639 (FL). The PET/CT instrument was supported by a NIH shared instrumentation grant S10OD025042.
Author information
Authors and Affiliations
Contributions
NP, LL, LZ, and JC did experiments, analyzed data and edited the paper; DJL, DAF, SLO, EDH, DJ supervised the studies, discussed the results and edited the paper. FL conceived the study, designed the experiments and prepared the paper.
Corresponding author
Ethics declarations
Competing interests
LZ, DAF, and FL have financial interests in AbCon Therapeutics, Inc, a Cleveland Clinic start-up company to commercialize the CD6-ADC technology.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Parameswaran, N., Luo, L., Zhang, L. et al. CD6-targeted antibody-drug conjugate as a new therapeutic agent for T cell lymphoma. Leukemia 37, 2050–2057 (2023). https://doi.org/10.1038/s41375-023-01997-8
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41375-023-01997-8
- Springer Nature Limited