TwoStep reports FDA clearance for first human trial of peptide-drug conjugate TS-104

TwoStep Therapeutics announced September 9 that the U.S. Food and Drug Administration had cleared its investigational new drug application for TS-104, a peptide-drug conjugate being developed for solid tumors. The company expects enrollment in a first-in-human Phase 1 trial to begin later in 2026, bringing a strategy for targeting several tumor-associated proteins closer to its first clinical test.

TwoStep also announced a $62.5 million Series A financing. The immediate significance is a funded path into human research. The announcement contains no patient results establishing that TS-104 is safe, shrinks tumors or improves survival, and the reported regulatory clearance does not constitute marketing approval.

A peptide carries the payload

TS-104 combines a polyspecific integrin-binding peptide, called PIP, with monomethyl auristatin E, or MMAE, a cytotoxic payload. Fierce Biotech independently reported the financing and described that pairing in its September 9 fundraising coverage.

The targeting concept addresses variation among cancer cells. TwoStep says its peptide recognizes five tumor-associated integrins rather than depending on one surface target. Whether that design produces useful selectivity and drug delivery in patients remains a clinical question.

Stanford’s account of the platform’s development provides the scientific background. Researchers engineered a knottin—a peptide stabilized by intertwined disulfide bonds—to bind tumor-associated integrins, then developed ways to attach therapeutic cargo. Integrins are cell-surface proteins; the attraction of recognizing several is the possibility of reaching tumors whose target expression varies.

That is a rationale for testing. It does not establish how much drug will reach human tumors, how much will reach healthy tissues, or whether the balance will yield a tolerable treatment.

Earlier laboratory evidence has clear boundaries

A peer-reviewed study published online in June 2016 demonstrated an earlier integrin-targeting knottin conjugate carrying gemcitabine. Researchers used laboratory cancer-cell models, including brain, breast, ovarian and pancreatic cancer cell lines, to examine binding, internalization, intracellular payload release and inhibition of cell proliferation.

The conjugate entered cells through an integrin-mediated process and inhibited proliferation. The investigators also reported that it bypassed a gemcitabine-resistance mechanism in pancreatic cancer cells. Those findings supported the feasibility of peptide-directed drug delivery in the experimental systems tested.

The paper studied a different payload and is historical background, not a clinical result for TS-104. Cell-culture activity cannot establish patient benefit or predict the full toxicity of a conjugate. Several authors disclosed that they were inventors on Stanford-owned intellectual property related to the technology, a relevant interest when interpreting the work.

What the clearance establishes

FDA’s description of the IND process explains the regulatory threshold. An application includes preclinical pharmacology and toxicology, manufacturing information, and proposed clinical protocols. The agency assesses whether initial testing would expose research participants to unreasonable risk.

That process permits investigation; it does not settle the questions the investigation is intended to answer. TwoStep’s announcement identifies the planned study as first-in-human Phase 1 but does not provide a detailed endpoint hierarchy, planned enrollment count or complete eligibility criteria. It also does not report that a participant has already received TS-104.

Consequently, the eventual population and protocol will matter when results become available. Any early activity signal will need to be interpreted alongside adverse events, treatment exposure, tumor type and the study’s design. Results from an initial trial would also need appropriate follow-up before supporting broader claims about efficacy.

For the peptide field, the development is a concrete transition toward clinical evaluation of a multi-target delivery platform. For patients, the unresolved issue is whether that molecular design can produce meaningful tumor control with an acceptable safety profile. The financing and reported IND clearance make that question testable; they do not yet answer it.