Anti-Müllerian hormone type II receptor (AMHR2/MISIIR) is a $TGF$-$\beta$ receptor superfamily member, whose ligand AMH plays an essential role in fetal sexual development. While expressed at low levels in healthy ovarian and testicular tissues , AMHR2 is frequently upregulated in a range of human malignancies. Immunohistochemical (IHC) analyses demonstrate that AMHR2 protein is detectable in approximately 70% of primary epithelial ovarian cancers (EOC) and 53% of colorectal cancers (CRC) [Gama et al., Biology 2020, 10(1):3]. Despite acceptable safety profiles and preliminary anti-tumor activity in Phase 1–2 clinical trials, anti-AMHR2 Mabs showed only modest efficacy, indicating substantial unmet medical needs for patients with AMHR2-positive solid tumors. Thus, AMHR2 represents a promising target for T-cell engager (TCE)-based immunotherapy.
We designed CRB2104, a novel 2:1 AMHR2×CD3 T-cell engager with bivalent high-affinity AMHR2-binding arms and an affinity-optimized CD3 binder, to mediate potent tumor-specific T-cell cytotoxicity with minimized CRS risk. Preclinical characterization included cell-binding assays, SPR affinity analysis, TDCC assays, cytokine profiling, efficacy in hPBMC- and HSC-engrafted xenograft models, and NHP safety assessment.
CRB2104 features a rationally designed 2:1 format with bivalent AMHR2 arms for enhanced avidity. Matched-format comparison of our proprietary M137 CD3 arm (hBA7) versus SP34 (BA3) demonstrated comparable AMHR2 binding but attenuated CD3 affinity for hBA7. Despite weaker T cell activation, hBA7 retained picomolar TDCC potency comparable to BA3, with markedly reduced target-independent cytokine release. These properties translated into robust antitumor efficacy in both HSC-humanized and PBMC-reconstituted mouse models, and a favorable safety profile with minimal cytokine elevation in NHPs.
CRB2104 (hBA7), a 2:1 AMHR2/CD3 TCE with an affinity-optimized CD3 arm, exhibits potent antitumor efficacy in humanized mouse models and a favorable safety profile in NHPs, supporting further development toward clinical translation.
