Abstract A058: Selective targeting of T regulatory cells by a TCR-mimic monoclonal antibody specific for foxp3-derived epitopes

Abstract

Immunosuppression by tumor-induced regulatory T (Treg) cells present major obstacles for successful immunotherapy. Treg expansion and its negative prognostic impact represent a general phenomenon seen in multiple types of cancer. Therefore, developing strategies for Treg depletion could enhance the reactivation of immune responses against the malignant tumor cells. However, the strategies of depleting Tregs have been hindered by the lack of specificity, which also leads to the depletion of anti-tumor effector cells. The transcription factor forkhead box p3 (FoxP3) is selectively expressed in and is essential to the suppressive function of Treg cells. FoxP3 thus would be an appealing target for eliminating Treg cells. However, Foxp3 is an undruggable intracellular protein. Here, we took a novel and unconventional approach to target Foxp3 by using a T cell receptor mimic (TCRm) mAb, which recognizes a human Foxp3-derived CD8 T cell epitope, presented by HLA-A*02:01 molecule. We show that the Foxp3 mAb specifically bound to CD4+CD25^hiCD127^lo Foxp3+ Treg cells from HLA-A0201 positive donors, and tumor cell lines co-expressing Foxp3 and HLA-A*02;01 molecule. Both afucosylated Fc enhanced human IgG1 and bispecific T cell engager formats of the Foxp3 mAb are able to kill in vitro-generated Treg clones from HLA-A0201+ donors and “Treg-like” cutaneous lymphoma cells (HLA-A*02:01+) that have a high level expression of CD4, CD25 and Fox3+. FoxP3-targeting antibodies could potentially be a novel approach in cancer immunotherapy by overcoming immunosuppression caused by Tregs and tumor cells expressing Foxp3.

Citation Format: Tao Dao, Casey Jarvis, Andrew C. Scott, Tatyana Korontsvit, Victoria Zakhaleva, Dmitry Pankov, Manuel Direito de Morais Guerrerio, Melissa Mathias, Neal Cheng, Cheng Liu, David A. Scheinberg. Selective targeting of T regulatory cells by a TCR-mimic monoclonal antibody specific for foxp3-derived epitopes [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A058.