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Abstract Colorectal cancer (CRC) is the fourth leading cause of death in the world with a global mortality rate of over 700, 000 annually. While recent advancement in diagnosis and prevention has reduced the overall number of deaths, the lack of effective and durable treatment has not significantly improved survival rate. Emerging modalities in immunotherapy such as T cell engagers have paved new ways for disease management. However, a common challenge to advancing T cell engagers in the clinic is poor target specificity and high toxicity associated with non-specific T cell activation and cytokine release. To overcome these shortcomings, we have developed QL335, a bispecific antibody bridging LY6G6D antigen on tumor cells and CD3 on T cells. LY6G6D or Lymphocyte Antigen 6 Family Member G6D, is a GPI-anchored membrane protein that, according to TCGA RNAseq data, is highly expressed in microsatellite stable (MSS) colorectal cancer but not in normal tissues. We analyzed LY6G6D expression by IHC in over 200 CRC patient tumors and 40+ normal tissue samples from different organs, confirming its highly restricted CRC expression pattern. We constructed our bispecific antibody in a 2+1 format, comprising two high affinity LY6G6D binding domains and one reduced affinity CD3 binding domain. Such format allows for higher tumor accumulation while mitigating non-specific T cell activation in the periphery. In vitro evaluation showed that QL335 induced potent yet highly specific T cell activation and killing of only target cells expressing LY6G6D. QL335 demonstrated robust anti-tumor efficacy in vivo against human colon cancer xenograft models with human PBMC reconstitution. Importantly, QL335 was well tolerated in cynomolgus monkeys dosed up to 50 mg/kg, supporting the enhanced safety profile by design of this therapeutic candidate. QL335 is currently being evaluated in a phase 1 clinical trial. Citation Format: Shenda Gu, Guangjie Guo, Helena Yee, Hieu V. Tran, Shihao Chen, Chuanzeng Cao, Ke Liu, Chunyan Jin, Weihua Lun, Ruixue Ma, Lele Ren. QL335, a novel T cell engager with enhanced safety profile targeting MSS colorectal cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 6727.
Gu et al. (Fri,) studied this question.