Pfizer has presented compelling preclinical data for PF-08052666 (also known as HBM9033 or SGN-MesoC2), a first-in-class topoisomerase 1 inhibitor (TOP1i)-based antibody-drug conjugate (ADC) targeting mesothelin (MSLN), at the American Association for Cancer Research (AACR) Annual Meeting 2025. The novel therapeutic candidate, originally developed using Nona Biosciences' proprietary Harbour Mice® and integrated ADC platforms, demonstrated potent antitumor activity across multiple cancer types.
Pfizer acquired the global clinical development and commercialization rights to this promising ADC from Nona Biosciences on December 14, 2023, and is now advancing the compound through clinical development.
Novel Design Addresses Previous Limitations
PF-08052666 was specifically engineered to overcome limitations observed in earlier anti-MSLN ADCs. The drug consists of a human IgG1 monoclonal antibody conjugated to a potent camptothecin-based TOP1i payload with a protease-cleavable linker. A key innovation is its higher drug-to-antibody ratio (DAR) of 8, potentially enhancing its therapeutic efficacy.
The antibody component features carefully tuned binding properties that reduce interaction with soluble MSLN while maintaining strong binding and internalization to membrane-bound MSLN on cancer cells. This design innovation addresses a common challenge in targeting MSLN, which can be shed from tumor cells into circulation.
Impressive Preclinical Performance
The preclinical data presented at AACR 2025 highlighted several promising aspects of PF-08052666's performance:
In vitro studies demonstrated that the ADC delivers direct cytotoxicity to MSLN-positive cells while also exhibiting bystander killing activity on neighboring MSLN-negative cells. Importantly, it maintained its cytotoxic effects even in the presence of physiologically relevant concentrations of soluble MSLN, which has been a limitation for previous MSLN-targeting therapies.
In vivo testing showed PF-08052666 outperforming a DM4-based anti-MSLN benchmark ADC in both cell-line and patient-derived xenograft models across multiple tumor types, including ovarian, lung, and colorectal cancers. These tumor types represent significant areas of unmet medical need, particularly for patients with advanced disease.
Perhaps most notably, the compound demonstrated superior efficacy in heterogeneous xenograft models containing both MSLN-positive and MSLN-negative cells. This finding highlights the enhanced bystander activity of PF-08052666's novel linker-payload system, suggesting potential efficacy against tumors with variable MSLN expression.
Advancing to Clinical Trials
Based on these promising preclinical results, PF-08052666 has advanced to a first-in-human Phase 1 clinical trial (NCT06466187) in patients with advanced solid tumors. The trial is currently enrolling participants and will evaluate the safety, tolerability, and preliminary efficacy of this novel therapeutic approach.
"The preclinical data on PF-08052666 presented by Pfizer at AACR 2025 reflects the strength of our technology platforms and our dedication to advancing transformative therapies," said Jingsong Wang, MD, PhD, Chairman of Nona Biosciences. "By leveraging our industry-leading technology platforms, we continue to drive innovation that enables the development of next-generation biotherapeutics. We look forward to further collaboration with Pfizer to accelerate breakthroughs that address critical medical needs."
Targeting Mesothelin: A Promising Approach
Mesothelin represents an attractive target for cancer therapy as it is a tumor-associated antigen upregulated in various solid tumors but has limited expression in normal tissues. This expression profile potentially allows for tumor-specific targeting while minimizing off-target effects.
Previous attempts to target MSLN have faced challenges, including interference from soluble MSLN and limited efficacy. PF-08052666's innovative design appears to address these limitations, positioning it as a potential best-in-class therapeutic option for MSLN-expressing cancers.
Collaborative Innovation
The development of PF-08052666 highlights the value of collaborative innovation in advancing cancer therapeutics. Nona Biosciences' proprietary Harbour Mice® platform, which generates fully human monoclonal antibodies, provided the foundation for this promising ADC.
The partnership between Nona Biosciences and Pfizer combines cutting-edge antibody discovery technology with global clinical development capabilities, potentially accelerating the path to bringing this novel therapy to patients with difficult-to-treat solid tumors.
As the Phase 1 trial progresses, oncologists and patients will be watching closely to see if the impressive preclinical results translate into clinical benefit for patients with MSLN-expressing cancers.
