Development of a Bispecific Antibody Based Immunotherapy for Triple Negative Breast Cancer

Development of a Bispecific Antibody Based Immunotherapy for Triple Negative Breast Cancer SUMMARY ABSTRACT A promising and versatile approach to cancer treatment is the use of bispecific antibodies bsAb for immune cell redirection In the two clinically approved therapies that pioneered this strategy a bsAb drug acts as a molecular bridge between a T cell via CD binding and a tumor cell via binding of a tumor associated antigen or TAA Simultaneous binding of both targets results in T cell mediated cytolysis of the tumor cell The impressive success of this strategy has led to the development of similar bsAb immunotherapies for a wide variety of both hematological and solid cancers resulting in over drugs in active clinical trials Triple negative breast cancer TNBC is an invasive breast cancer defined by a lack of the three distinct TAA required for available targeted breast cancer therapies The lack of a robust TAA for TNBC has resulted in a dearth of modern targeted therapies and poor patient outcomes and therefore development of novel TAA targeted drugs for TNBC is a significant unmet medical need OncoTAb Inc has developed a proprietary antibody TAB that recognizes a tumor specific variant of MUC tMUC This antibody serves as the basis of OncoTAb s Agkura Personal Score diagnostic test and has high specificity for a broad number of TNBC cell lines In this proposal we will develop and test a bsAb based immunotherapy for TNBC derived from the TAB antibody Historically development of novel bsAb immunotherapies relies on the use of antibody fragments or complicated post processing and purification both of which can reduce stability hinder manufacturability and prolong development In order to alleviate these development hurdles Dualogics LLC has developed a proprietary bsAb platform called OrthoMab that retains the stability and manufacturability of native antibodies and is compatible with existing antibody sequences Using the OrthoMab platform we can rapidly generate a suite of bsAb molecules with varied size binding valency and geometric orientation all of which have been shown to modulate the efficacy of bsAb immunotherapies In Specific Aim of this proposal we will generate and biophysically characterize three bsAb specific for tMUC and CD each with unique pharmacokinetic and functional properties Ryan Hallett Dualogics LLC In Aim we will measure specificity of each bsAb for TNBC cell lines and demonstrate targeted cytolysis of tumor cells by human PBMCs Lloye Dillon OncoTAb Inc In Aim we will assess the pharmacokinetic properties of our top performing bsAb to determine dosing and evaluate efficacy in a TNBC xenograft mouse model Ru Zhou UNC Charlotte These experiments will validate T cell redirection by tMUC as a viable strategy for TNBC treatment and establish the basis of a phase II study to pursue further clinical development and pre IND studies Narrative Bispecific antibodies that initiate tumor specific immune response are among the most effective immunotherapies on the market today and are being widely developed for most cancers Despite the expansion of these therapeutics in recent years there is still no specific and effective immunotherapy for triple negative breast cancer TNBC Using Dualogics OrthoMab bispecific antibody platform and OncoTAb s proprietary tumor specific MUC tMUC antibody we will generate a panel of T cell redirecting bispecific antibodies and demonstrate therapeutic efficacy in mouse models of TNBC