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IMMUNOTHERAPY

CD6-targeted antibody-drug conjugate as a new therapeutic agent for T cell lymphoma

Leukemia volume 37, pages 2050–2057 (2023)Cite this article

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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.

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Fig. 1: TCL specimens express CD6 at high levels on TCL cells.
Fig. 2: Development of CD6-ADC that kills TCL cells in vitro.
Fig. 3: A single dose of systemic CD6-ADC prevents the development of tumors in a preclinical model of TCL.
Fig. 4: A single dose of CD6-ADC systemic or local treatment shrank established tumors in a preclinical model of TCL.
Fig. 5: Humanization of the anti-CD6 mAb and examination of the treatment efficacy of humanized CD6-ADC.

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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.

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Authors and Affiliations

  1. Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    Neetha Parameswaran, Joel Chen, Deepa Jagadeesh & Daniel J. Lindner

  2. Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

    Liping Luo, Lingjun Zhang & Feng Lin

  3. Department of Nuclear Medicine, Imaging Institute, Cleveland Clinic, Cleveland, OH, USA

    Frank P. DiFilippo

  4. Small Animal Imaging, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

    Charlie Androjna

  5. Division of Rheumatology and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, MI, USA

    David A. Fox

  6. Department of Laboratory Medicine, Cleveland Clinic, Cleveland, OH, USA

    Sarah L. Ondrejka & Eric D. Hsi

Authors
  1. Neetha Parameswaran
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  2. Liping Luo
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  3. Lingjun Zhang
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  4. Joel Chen
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  10. Deepa Jagadeesh
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  11. Daniel J. Lindner
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  12. Feng Lin
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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

Correspondence to Feng Lin.

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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.

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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

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