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Background Tumor-targeting technologies like ADCs deliver cytotoxic drugs to tumors while minimizing exposure to healthy tissue. However, most ADCs bind to a single tumor-associated marker and are only applicable to certain oncology indications. There is a need for novel strategies with broader applicability across different tumor types.TwoStep Therapeutics’ technology is built around a versatile targeting peptide ‘PIP’ that binds selectively to multiple tumor-associated integrins (including αvβ3, αvβ5, αvβ6, αvβ1 and α5β1), a unique feature that enables it to deliver payloads to virtually any solid tumor. PIP preferentially binds to active integrin conformations that are abundant in tumor tissue, further enhancing its specificity and safety.Methods PIP-MMAE is a fully synthetic knottin peptide-drug conjugate composed of the tumor-targeting peptide ‘PIP’ conjugated to the cytotoxic payload ‘MMAE’ using a clinically-validated linker. The conjugate was evaluated for in vivo efficacy in multiple human cancer cell-line derived xenograft models (CDX) and patient-derived xenograft models (PDX) after IV administration in BALB/c nude mice. PIP-MMAE efficacy was also benchmarked against clinical-stage drug conjugates for comparison. Finally, safety and PK of IV-dosed PIP-MMAE was evaluated in repeated-dose non-GLP toxicology studies in rats and cynomolgus monkeys.Results PIP-MMAE was broadly effective across CDX and PDX tumor models with varying target expression levels. In head-to-head studies, PIP-MMAE outperformed clinical-stage benchmarks BT8009 (Nectin-4-targeting peptide-MMAE conjugate; Bicycle Therapeutics) and SGN-B6A (αvβ6 integrin-targeting ADC-MMAE; Pfizer).In a head and neck cancer model with high αvβ6 integrin expression, strong initial responses were observed with SGN-B6A treatment, but tumors eventually became resistant and continued to grow even when additional doses were administered. In contrast, PIP-MMAE induced complete tumor regression with durable responses even weeks after the final dose was administered, indicating PIP-MMAE is not susceptible to the resistance mechanism observed with SGN-B6A. Furthermore, we found that PIP-MMAE was able to effectively treat tumors that had acquired resistance to SGN-B6A therapy.PK profiles of PIP-MMAE show rapid clearance of the parent conjugate from systemic circulation (as expected), while released MMAE is retained in tumors for days. Finally, in repeated-dose toxicology studies, PIP-MMAE was well tolerated in both rats and NHPs with no indication of any PIP-related (target-dependent) toxicities.Conclusions PIP-MMAE demonstrates robust efficacy across various solid tumors, alongside a ‘fast-in, fast-out’ PK profile that confers remarkable safety. These preclinical data support the continued development of PIP-MMAE, with clinical trials planned to further evaluate its safety, PK, and anti-tumor activity in cancer patients.Ethics Approval All the procedures related to animal handling, care and the treatment in the study were performed according to the guidelines approved by the Institutional Animal Care and Use Committee (IACUC) of WuXi AppTec, following the guidance of the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC).