Abstract LB230: Generation of a B7-H4-restricted LTBR agonist to induce tertiary lymphoid structure formation in solid tumors

Abstract Tertiary lymphoid structures (TLS) are lymph node-like structures that form in response to inflammation and facilitate immune activation within the local microenvironment. TLS prevalence in solid tumors has been associated with more favorable prognosis and response to immune checkpoint inhibitors, findings that have led to the hypothesis that inducing TLS formation in tumors has significant therapeutic potential. Lymphotoxin beta receptor (LTBR) is a member of the tumor necrosis factor (TNF) receptor superfamily and is activated upon binding to lymphotoxin αββ (LTαββ) or LIGHT. Gain- and loss-of-function studies demonstrate LTBR serves as a key driver of both lymph node formation and homeostasis. Our goal was to develop a tumor-restricted, TLS-inducing therapeutic LTBR agonist that did not interfere with endogenous LTBR/ligand interactions. B7 homolog 4 (B7-H4) is B7 family ligand overexpressed in variety of solid tumor indications including lung, breast, ovarian, uterine, and cervical cancers; therefore, directing LTBR agonism in tumors via a B7-H4 targeting arm could address a substantial unmet patient need. To this end, we generated bispecific antibodies that targeted both LTBR and B7-H4 and screened them for B7-H4-dependent LTBR agonism. We identified a lead candidate, ABX4233, that simultaneously engages LTBR and B7-H4, without blocking LTBR binding to LTαββ or LIGHT, and exhibits B7-H4-dependent LTBR agonism with sub-nanomolar potency. ABX4233 activated cancer-associated fibroblasts and reprogrammed endothelial cells towards a phenotype that supports immune cell homing and lymphoid tissue development. In vivo, ABX4233 evoked dose- and B7-H4-dependent LTBR agonism in a homotypic xenograft tumor model. Furthermore, a mouse-reactive surrogate bispecific antibody elicited single agent efficacy, as well as enhanced response to anti-PD-1, in syngeneic B7-H4-expressing CT26 tumors. Mechanistically, surrogate bispecific antibody treatment was associated with high endothelial venule (HEV) content and lymphoid aggregates containing CD3+ T cells and CD19+ B cells, key features of TLS formation. Taken together, these data demonstrate LTBR agonism drives TLS formation within B7-H4-expressing tumors, resulting in anti-tumor efficacy. These results support clinical development of ABX4233 for cancers in which B7-H4 is overexpressed. Citation Format: Jiawei Huang, Jacqueline Tabor, Betty C. Li, Sindhuja Ramakrishnan, Helen Liu, Kikuye Koyano, Bin Fan, Alan Kutach, Rujin Cheng, Ali Khateb, Jonathan B. Johnston, Noha Elabed, Leanne Wong, Roshni Nambiar, Matthias J. Scherr, Mark Humphrey, Jonathan Aguayo, Yadong Yu, Peng Wang, Alison Lucero, Peirong Chen, Kyle Tsukamoto, Meredith M. O'Conner, Andrew Goodyear, Curtis Lai, Leore T. Geller, Lisa K. Blum, Shuin Park, Nicole Malandro, Rick Feldman, Ursula Jeffry, Daniel D. Kaplan, Alessandro Palumbo, Jer-Yuan Hsu, Zimple Matharu, Lee B. Rivera. Generation of a B7-H4-restricted LTBR agonist to induce tertiary lymphoid structure formation in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB230.