Characterization of the first-in-class T-cell-engaging bispecific single-chain antibody for targeted immunotherapy of solid tumors expressing the oncofetal protein claudin 6

Abstract

The fetal tight junction molecule claudin 6 (CLDN6) is virtually absent from any normal tissue, whereas it is aberrantly and frequently expressed in various cancers of high medical need.We engineered 6PHU3, a T-cell-engaging bispecific single chain molecule (bi-(scFv)2) with anti-CD3/anti-CLDN6 specificities, and characterized its pharmacodynamic properties.Our data show that upon engagement by 6PHU3, T cells strongly upregulate cytotoxicity and activation markers, proliferate and acquire an effector phenotype. 6PHU3 exerts potent killing of cancer cells in vitro with EC50 values in the pg/mL range. Subcutaneous xenograft tumors in NSG mice engrafted with human PBMCs are eradicated by 6PHU3 treatment and survival of mice is significantly prolonged. Tumors of 6PHU3-treated mice are strongly infiltrated with activated CD4+, CD8+ T cells and TEM type cells but not Tregs and display a general activation of a mostly inflammatory phenotype.These effects are only observed upon bispecific but not monospecific engagement of 6PHU3. Together with the exceptionally cancer cell selective expression of the oncofetal tumor marker CLDN6, this provides a safeguard with regard to toxicity.In summary, our data shows that the concept of T-cell redirection combined with that of highly selective targeting of CLDN6-positive solid tumors is effective. Thus, exploring 6PHU3 for clinical therapy is warranted.

Antigen-specific oncolytic MV-based tumor vaccines through presentation of selected tumor-associated antigens on infected cells or virus-like particles

“…Both MV and VSV are clinically developed for virotherapeutic purposes against different tumor entities including ovarian carcinoma, which also reveal significant up-regulation of CLDN6 23 , 47 , and thus constitutes an ideal tumor vaccination target, too, since few auto-immunity is to be anticipated. Indeed, passive immunotherapy with anti-CLDN6 mAb (IMAB027) is currently under clinical development for patients with recurrent advanced ovarian cancer (NCT02054351).…”

NKG2D Ligand–Targeted Bispecific T-Cell Engagers Lead to Robust Antitumor Activity against Diverse Human Tumors

“…It has been shown that the T EM cell population expanded during treatment of ALL patients with blinatumomab, and T EM expansion was also shown in long term T cell cultures expanded with BiTE ESK-1 (31, 32). Treatment with 6PHU3, a BiTE that targets claudin 6, was also found to increase the population of T EM in the tumors of xenografted mice (33). The T EM cell population has also been shown to contribute to BiTE redirected target cell lysis.…”

Claudin‐targeted drug development using anti‐claudin monoclonal antibodies to treat hepatitis and cancer

“…Determining the complex structures of other CLDNs and anti‐CLDN antibodies with proven pharmaceutical utility will promote theoretical in silico drug design for CLDN‐targeted drug development. In addition, clinical trials of anti‐CLDN antibodies as antitumor reagents are ongoing, and several groups are developing and screening new types of CLDN binders …”

“…In addition, clinical trials of anti-CLDN antibodies as antitumor reagents are ongoing, and several groups are developing and screening new types of CLDN binders. [88][89][90][91] Acknowledgments This work was supported by a Health and Labour Sciences Research grant from the Ministry of Health, Labour, and Welfare of Japan; a grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (24390042); a grant from the Adaptable and Seamless Technology Transfer Program through targetdriven R&D, Japan Science and Technology Agency; a grant from the platform for drug discovery, informatics, and structural life science of the Ministry of Education, Culture, Sports, Science, and Technology, Japan; a grant from the Japan Agency for Medical Research and Development; and the Takeda Science Foundation. Y.H.…”