Work

938 A spatially optimized long-acting gp100×CD3×albumin trispecific antibody enables durable antitumor immunity in gp100-expressing solid tumors

Year: 2026

Type: conference-abstract

Abstract: Background T-cell engagers (TCEs) targeting the gp100/HLA-A*02:01 complex have demonstrated significant clinical potential; however, the efficacy of conventional short-acting TCEs is frequently limited by brief systemic exposure, excessive cytokine release, and the progressive loss of functional T cells following repeated activation. To address these challenges, we developed a fully human gp100×CD3×albumin trispecific antibody designed to combine potent tumor targeting, controlled T-cell activation, and prolonged in vivo exposure for the treatment of gp100-expressing malignancies.Methods A fully human TCR-mimic (TCRm) antibody recognizing the gp100/HLA-A02:01 complex was generated using the RenTCR-minic™ platform. The resulting trispecific molecule was engineered to maintain target engagement while minimizing steric interference upon albumin binding. Binding kinetics, cytokine release, and cytotoxicity were evaluated in vitro and compared with a short-acting gp100-targeted bispecific benchmark. Pharmacokinetics (PK) were assessed in hFcRn/hALB double-humanized mice. Antitumor efficacy, T-cell persistence, and immune phenotypes were evaluated in PBMC-humanized mice bearing engineered gp100+/HLA-A02:01+ solid tumor xenografts.Results The trispecific antibody demonstrated strong, specific binding to the target complex and mediated potent T-cell cytotoxicity. In vitro, the molecule significantly reduced IFN-γ release compared to the short-acting benchmark while maintaining superior tumor-killing activity, indicating an improved therapeutic index. In double-humanized mice, albumin engagement extended functional systemic exposure from hours to over two weeks and substantially blunted peak drug exposure. In PBMC-humanized tumor models, the conventional short-acting treatment induced marked activation-induced cell death (AICD) of T cells. In contrast, our optimized trispecific antibody acted as a homeostatic engine, driving robust and steady-state T-cell expansion within the tumor microenvironment and reversing exhaustion. Phenotypic analysis of PD-1 and TIM-3 expression revealed no evidence of elevated T-cell exhaustion. Ultimately, these pharmacokinetic and immunological advantages translated into complete and durable tumor eradication, effectively preventing the late-stage tumor regrowth observed in the short-acting benchmark cohort.Conclusions By integrating highly specific antigen recognition, an optimized spatial geometry for CD3 engagement, and albumin-mediated half-life extension, this trispecific antibody achieves durable antitumor activity against gp100-expressing solid tumors while mitigating excessive cytokine release and T-cell exhaustion. These findings strongly support its potential as a next-generation T-cell engager with a superior pharmacokinetic and immunological profile.

Source: Journal for ImmunoTherapy of Cancer

DOI: 10.1136/jitc-2026-sitc2026.0938