CD6-Targeted Antibody-Drug Conjugate As a Potential Therapeutic Agent for T Cell Lymphomas

• Published in: Blood 2021-11, Vol.138 (Supplement 1), p.1193-1193
• Main Authors: Parameswaran, Neetha, Luo, Liping, Zhang, Lingjun, Chen, Joel, Fox, David A, Hsi, Eric D., Jagadeesh, Deepa, Lin, Feng
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2021-146855

Introduction: Peripheral T-cell lymphomas (PTCLs) comprise a subset of blood cancers that are molecularly heterogeneous and often associated with poor survival. While brentuximab vedotin has shown efficacy in CD30-expressing lymphomas such as anaplastic large cell lymphoma, effective targeted therapies for PTCLs are lacking and this represents an unmet medical need. CD6, an established surface marker for T cells, is a key regulator of T cell responses. CD6 has been suggested as a target for treating T cell-mediated autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis. We previously reported that CD6 knockout mice show reduced pathogenic T-cell responses and thus are protected against several models of autoimmune diseases. We also found that CD6 could be targeted therapeutically by anti-CD6 mAbs in these mouse models of autoimmune diseases. Although the distribution of CD6 and its role in regulating normal, non-malignant T-cells has been established, the expression of this marker on PTCL cells and its potential use as a selective targeted therapeutic agent for PTCLs has not been explored. METHODS: To determine the expression profile of CD6 on the malignant T-cells, different specimens including established T-cell lymphoma/leukemia cell lines HH, MOLT-4, HUT-78 and JurkaT-cells, as well as PTCL patient-derived xenografts (PDX) were analyzed for CD6 expression by flow cytometry using UMCD6, a high-affinity anti-human CD6 mAb. Besides, a custom-made tissue microarray containing biopsy samples from different PTCL patients was also evaluated by immunohistochemical staining using the same mAb. A CD6-targeted antibody-drug conjugate (CD6-ADC) was prepared by conjugating monomethyl auristatin E (MMAE), a potent antimitotic toxin successfully used in other FDA-approved ADCs, to UMCD6. Control non-binding ADC was prepared the same way using purified mouse IgGs. The potency of the CD6-ADC of killing PTCL was first evaluated in vitro using HH and HUT78 cells with trypan blue staining. For in vivo treatment studies, NSG mice were subcutaneously inoculated with HH cells, then treated with CD6-ADC or controls at different time points either systemically by intraperitoneal injections or locally by intratumor injections. Treatment efficacies were evaluated by measuring subcutaneous tumor volumes and detecting metastasized tumors in bone marrows, spleens and livers. RESULTS: Our flow cytometric and immunohistochemical staining studies showed that most, if