Abstract Background: The therapeutic antibody field has been predominantly anchored in the kappa (κ) light chain repertoire, resulting in the systematic underutilization of the lambda (λ) light chain, a component that constitutes approximately 40% of the natural human antibody landscape. This oversight directly constrains the breadth of discoverable therapeutics. The development of fully human λ antibodies is based on the biology of light chain rearrangement, a process in which λ-rearrangement serves as an essential compensatory pathway upon κ-rearrangement failure. This establishes λ chains as fundamental for antibody repertoire completeness and adaptability, not merely supplementary. Method: Our company has developed a series of RenMice platforms, including RenMab™ mice capable of generating antibodies with κ light chains. By employing Biocytogen's unique Mb-scale chromosome engineering technology, we successfully integrated the 1. 1 Mb human λ light chain locus into C57BL/6J embryonic stem cells (ESCs). Subsequent breeding yielded fully humanized mice carrying humanized heavy, κ, and λ chains, thereby achieving comprehensive humanization of the immunoglobulin system. To further enhance the platform’s robustness and better model the polygenic nature of human immune responses, we diversified the genetic background of the RenMice strains through systematic backcrossing into multiple standard inbred backgrounds, including BALB/c and SJL. Results: This approach yielded two novel models: the RenMab HKL mouse, which expresses human κ and λ chains, and the RenMab HL mouse, which exclusively expresses the human λ chains. Extensive immune phenotyping validated that all models maintain fully competent, wild-type-like immune system development and homeostasis. A key finding was that the RenMab HKL mice faithfully recapitulated the natural human κ: λ light chain expression ratio (nearly 1: 1). Both models exhibited highly diverse, pre-immune λ antibody repertoires with distinct germline gene segment usage preferences. Upon immunization, both strains reliably generated high-affinity, antigen-specific, fully human λ antibodies, with binding affinities competitive with established therapeutic benchmarks. The introduction of diversified genetic backgrounds contributed an additional layer of immune repertoire variation, enriching the discoverable antibody space. Conclusion: We have established a next-generation platform for fully human λ antibody generation. The RenMab HKL and HL models significantly expand the antibody repertoire diversity, thereby facilitating the discovery of novel therapeutic biologics against refractory targets and advancing the development of innovative immunotherapies. Citation Format: Benny Yang, Lili Liu, Lijun Zhang, Yanshuang Li, Huizhen Zhao, Jiawei Yao. Unlocking the Full Human Antibody Repertoire: Novel Humanized Antibody Mouse Models with Fully Humanized Lambda Chains and Diversified Genetic Backgrounds abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB052.
Yang et al. (Fri,) studied this question.