Abstract A62: Three pronged strategy to enhance pharmacological effectiveness of pHLA targeting TcEs

Abstract T-cell engagers redirect T cells to a tumor specific target leading to lysis of tumor cells with demonstrated therapeutic benefit in hematological and solid tumors. Most T-cell engagers in development focus on surface exposed tumor antigens as targets. However, HLA/peptide complex directed (TCR mimic) T cell engagers enable targeting of tumour associated intracellular proteins and therefore broaden the cancer antigen space for T cell engagers. Potency and specificity are key attributes for the design of TCR mimic T cell engagers. Here, we employed a three pronged strategy to enhance pharmacological effectiveness of pHLA targeting TcEs: i) innovative bispecific formats employing avidity effect ii) TCRm affinity maturation by pHLA-Fv model based library design and phage display iii) pHLA-Fv crystal structure based affinity maturation in silico. The different strategies and combinations thereof enabled and improved lysis of tumor cells by T cell engager and informed on the structure-function relation of TCR mimic T cell engager. Citation Format: Nicolas Sabarth, Paul Adam, Sandeep Kumar, Yanyun Liu, Renate Konopitzky, Jark Boettcher, Tadas Panavas. Three pronged strategy to enhance pharmacological effectiveness of pHLA targeting TcEs [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A62.