Work

914 Dual-antigen targeting via a PMPC-engineered bispecific ADC overcomes tumor heterogeneity and enhances anti-tumor efficacy in advanced ovarian cancer

Year: 2026

Type: conference-abstract

Abstract: Background High-grade serous ovarian cancer (HGSOC) kills more women than any other gynecologic malignancy. Over 70% of patients relapse after first-line therapy, and no treatment currently achieves durable control in the platinum-resistant setting. Antibody-drug conjugates (ADCs) have generated excitement but remain constrained by four interrelated failures: single-antigen targeting allows tumor escape through antigen downregulation; off-target toxicity limits dosing; poor pharmacokinetics reduce tumor exposure; and inadequate penetration leaves disseminated micrometastases untreated. We asked whether combining bispecific antibody-drug targeting with polymer-shielded delivery could resolve all four simultaneously — in a single construct.Methods We screened a library of bispecific antibodies (bsAbs) and identified UAB28-3, a lead candidate with confirmed binding across six ovarian cancer cell lines and four independent HGSOC patient-derived tumor samples. UAB28-3 was conjugated with MMAE and DXd — two membrane-permeable, bystander-killing payloads — to generate bispecific ADCs (bsADCs) with mechanistically distinct cytotoxic mechanisms. To address systemic delivery, we applied our patented poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) polymer engineering platform, which shields the ADC during circulation through an anti-fouling surface coating and enables tumor microenvironment (TME)-triggered polymer removal via MMP-2/9-cleavable linkers. Efficacy was evaluated against HGSOC cell lines and patient-derived xenograft (PDX) tumors; pharmacokinetics, biodistribution, and intratumoral delivery were assessed in xenograft mouse models.Results UAB28-3-based bsADCs exceeded 100-fold greater potency than T-DXd and T-MMAE — two leading clinical-stage ADCs — across HGSOC cell lines by IC50. PMPC engineering doubled plasma half-life and substantially reduced off-target accumulation in the liver and spleen compared to non-engineered controls. In human ovarian cancer cell xenograft models, PMPC-engineered ADCs achieved 34% greater intratumoral drug signal at 24 hours post-injection and produced superior tumor control over both unmodified bsADC and monospecific ADC comparators. Neither the bispecific format nor PMPC engineering introduced detectable systemic toxicity at therapeutic doses.Conclusions A single PMPC-engineered bsADC construct outperforms leading clinical ADCs in potency, overcomes antigen heterogeneity through dual targeting, doubles systemic circulation, and concentrates drug selectively within the TME — without added toxicity. These findings establish a new ADC design principle with direct translational relevance for platinum-resistant HGSOC. Clinical development is being advanced through NanoBridge Therapeutics, Inc.

Source: Journal for ImmunoTherapy of Cancer

DOI: 10.1136/jitc-2026-sitc2026.0914