In this project we propose to develop a first-in-class therapeutic antibody (Ab) against high grade serous carci- noma (HGSC) composed of two domains that simultaneously target separate epitopes (biparatopic) of the FRα antigen coupled to a unique T-cell activating anti-CD3 moiety that mediates tumor kill with minimal cytokine secretion and preferentially activates effector over regulatory T cells. HGSC is the leading cause of gynecologic cancer mortality in women, with 22,240 new diagnoses and 14,070 deaths per year and <30% overall survival in advanced stage disease. Thus, there is an urgent medical need for novel, paradigm-shifting therapies. Nu- merous studies have shown that folate receptor α (FRα) is highly overexpressed in HGSC, whereas it is absent or minimally expressed in normal tissues. As such several Ab-based therapies targeting FRα have been devel- oped, most notably T-cell redirecting bispecific Abs (T-BsAbs) approaches that have shown some efficacy. How- ever, in HGSC these approaches have been hampered by toxicity including cytokine release syndrome (CRS), and formation of anti-drug immune responses. Teneobio makes fully human heavy chain only Abs (UniAbs) using a unique high throughput next generation sequencing (NGS)-based bioinformatics pipeline (TeneoSeek) and proprietary UniAb-producing animals (UniRats) that enable development of novel therapeutics by combining different mechanisms of action to address common impediments in the development of therapeutic Abs. The fully human heavy chain only structure of UniAbs facilitates multivalency and promotes stability and potentially limits anti-drug immune response concerns, as demonstrated by our BCMAxBCMAxCD3 trivalent, bispecific Ab that is on track to enter the clinic this year. Most importantly, we have used TeneoSeek to develop a novel αCD3 Ab that mediates tumor kill with minimal cytokine secretion (potentially limiting CRS) and preferential activation of effector over regulatory T cells. For these reasons, we hypothesize that a trivalent T-BsAb with biparatopic targeting of FRα coupled to our novel αCD3 moiety will provide high specificity with minimal cytokine secretion, potentially creating a safe and effective therapy for HGSC. In this application we will use our platform to identify two anti-FRα moieties with optimal functional characteristics targeting non-overlapping epitopes, combine them with our selectively-activating αCD3 domain, and select for the candidate with optimal safety and efficacy in in vitro, in vivo and ex vivo models of HGSC. In Specific Aim #1 we will use TeneoSeek to identify several hundred putative FRα-specific Ab sequence families. From among them we will identify UniAbs that bind non-overlapping epitopes with optimal functional characteristics, using a 2-step functional screen and competitive binding exper- iments. In Specific Aims #2 and #3 we will combine two of these binding domains specific for non-overlapping epitopes with our unique selectively-activating αCD3 moiety and choose a lead with optimal safety and efficacy in in vitro, in vivo and ex vivo models of HGSC. At the conclusion of Phase I, we will be ready to perform PK and IND-enabling studies in NHP in preparation for an IND filing and Phase 1 clinical trials in HGSC patients.
Public Health Relevance Statement: NARRATIVE High grade serous carcinoma (HGSC) is the leading cause of gynecologic cancer mortality in women. Therapeutic options for HGSC are limited with <30% overall survival in advanced stage disease. We propose to develop an antibody therapy for HGSC that combines two highly specific heavy chain-only antibody domains against non-overlapping epitopes of a tumor specific antigen with a unique T-cell activating domain to generate a novel therapy with reduced toxicity, improved efficacy and a widened therapeutic window.
Project Terms: Address; Affinity; Animals; Antibodies; Antibody Therapy; Antigens; B cell repertoire; base; Binding; Bioinformatics; Bispecific Antibodies; Carcinoma; CD3 Antigens; CD8B1 gene; Cell-Mediated Cytolysis; Cells; Cessation of life; Characteristics; Clinic; Competitive Binding; Coupled; cross reactivity; cytokine; cytokine release syndrome; Cytotoxic T-Lymphocytes; Development; Diagnosis; Disease; effective therapy; Epitopes; Evaluation; experimental study; Family; Flow Cytometry; folate-binding protein; Future; Generations; Grant; Half-Life; Human; Immune; immune activation; Immune response; Immunize; Immunotherapy; improved; In Vitro; in vivo; in vivo Model; Lead; Liquid substance; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Mediating; Medical; Modeling; mortality; neoplastic cell; next generation sequencing; Normal tissue morphology; novel; novel therapeutics; outcome forecast; overexpression; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Platinum; Preparation; recruit; Regulatory T-Lymphocyte; Relapse; Rodent; Safety; Sampling; screening; Serous; Specificity; Structure; Structure of germinal center of lymph node; T-Cell Activation; T-Lymphocyte; targeted treatment; Therapeutic; Therapeutic antibodies; therapeutic development; Tissues; Toxic effect; Toxicity due to chemotherapy; tumor; Tumor Antigens; Tumor-Deri
