Abstract 2077: Preclinical characterization of a next-generation CD19/CD3-bispecific T cell engager with extended serum half-life and superior potency against CD19-low target cells
Authors: Baeuerle Patrick A. , Mehta Naveen K. , Meetze Kristan , Li Bochong , Michaelson Jennifer S. 
Published: June 2022

T cell therapies targeting the B cell antigen CD19 have profoundly changed the way we treat various B cell malignancies. Both the CD19-specific T cell-engaging bispecific antibody blinatumomab and various autologous CAR-T cell therapies have exhibited robust clinical activity in relapsed/refractory acute lymphocytic leukemia (ALL) and non-Hodgkin lymphoma (NHL). While CAR-T cell therapies show high complete response rates, bispecific antibodies have room for improvement. Both therapies, however, fail in patients where tumor cells escape selective pressure by expressing very low or undetectable levels of the CD19 antigen.We developed a novel CD19/CD3-bispecific antibody construct called CLN-978. Like blinatumomab, CLN-978 has tandemly arranged CD19- and CD3-specific single-chain Fv (scFv) fragments. Uniquely, a single-domain antibody specific for serum albumin was N-terminally fused to enable a prolonged serum half-life, eliminating the need for continuous IV infusion. CLN-978 is composed of novel humanized CD19-, CD3- and albumin-binding elements that are cross-reactive with non-human primate (NHP) orthologs and lacks a hexahistidine tag. It is produced at g/L levels in CHO cells and enables protein A affinity purification. CLN-978 has a 100-fold higher binding affinity for CD19 than blinatumomab. Side-by-side comparison with blinatumomab showed that the higher CD19 binding affinity translates into superior T cell-mediated cytotoxicity (TDCC) of CLN-978 with both target cell lines expressing high or very low levels of CD19. Superior efficacy was similarly observed in xenotransplant mouse tumor models. Preclinical studies in primates are in progress assessing safety, pharmacology, pharmacokinetics (PK) and pharmacodynamics (PD) of CLN-978 administered either through intravenous or subcutaneous delivery. CLN-978 has the potential to have superior TDCC against cells expressing very low levels of CD19 as are selected following treatment with CD19-directed therapies. This may translate into higher response rates and longer response duration in ALL and NHL patients expressing normal and very low levels of CD19 on malignant B cells. The cross-reactivity of CLN-978 to the NHP orthologs of CD19, CD3 and albumin enables assessment of depletion of normal B cells, strategies to mitigate cytokine release, PK and PD properties, and exploration of dosing routes. CLN-978 holds promise as a CD19-targeted therapeutic that can be easily and conveniently administered to patients with diverse B cell malignancies.

Citation Format: Patrick A. Baeuerle, Naveen K. Mehta, Kristan Meetze, Bochong Li, Jennifer S. Michaelson. Preclinical characterization of a next-generation CD19/CD3-bispecific T cell engager with extended serum half-life and superior potency against CD19-low target cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2077.