Preclinical data presented at the World ADC San Diego meeting show that incorporating Lisata’s iRGD cyclic peptide, certepetide, as a non-cytotoxic payload in Catalent’s SMARTag antibody-drug conjugates improved antitumor efficacy and broadened intratumoral distribution of the cytotoxic payload. The findings also indicated enhanced tumor-selective penetration compared with the comparator constructs, according to a summary shared by the companies.
The core development is Catalent’s use of certepetide and analogs as part of its SMARTag “Enhanced Conjugates” concept, which pairs a conventional cytotoxic payload with a non-cytotoxic, tumor-penetrating payload that activates a transport pathway within the tumor microenvironment. Lisata has licensed certepetide to Catalent for this application. While certepetide has been clinically explored as a co-administered adjunct to chemotherapy, this approach embeds the peptide into the ADC architecture to potentially move the payload deeper into solid tumors where antigen density and perfusion are heterogeneous.
Strategically, this is a differentiation play in a crowded ADC market where sponsors are pushing drug-to-antibody ratios, dual warheads, and bystander effects to overcome distribution limits—often at the cost of therapeutic index and CMC complexity. A non-cytotoxic payload that improves tissue penetration without increasing systemic toxicity could raise response ceilings for existing targets and revive assets that have plateaued in efficacy. For Catalent, it extends the value of site-specific conjugation beyond manufacturing precision to biologic function. For Lisata, embedding certepetide into partner platforms broadens optionality beyond its own trials and converts a tumor-penetration biology into a licensable module that can travel across modalities.
If adoption follows, the ripple effects reach across the execution chain. Sponsors contemplating “Enhanced Conjugates” should expect new CMC workstreams: defining conjugation stoichiometry for dual payloads, establishing potency assays that capture both cytotoxic and transport functions, and demonstrating stability and release characteristics under ICH conditions. PK/PD models will need to incorporate peptide-mediated transport kinetics, not just linker cleavage and payload liberation, and bioanalytical methods must quantify multiple payloads in plasma and tissue. CROs and sites can anticipate protocols with biodistribution endpoints—such as imaging, paired biopsies, and spatial transcriptomics—that add operational complexity and require specialized pathology and cold-chain logistics. Regulators will focus on immunogenicity of the cyclic peptide, off-tumor activation of the transport pathway, and comparability if sponsors retrofit existing ADCs with the additional payload. Vendors in analytics and linker chemistry could see demand shift toward assays and chemistries optimized for multi-functional constructs.
The near-term signals to watch are translation: an IND for a first-in-human ADC embedding certepetide, target selection that emphasizes penetration (e.g., fibrotic solid tumors), and early pharmacodynamic evidence of deeper payload distribution at clinically tolerable doses. Dose-finding will need to disentangle the peptide’s contribution from the cytotoxin, potentially using imaging or intratumoral concentration measurements. Manufacturing scalability and batch-to-batch consistency for dual-payload DARs remain nontrivial risks, as does the potential for unexpected immunogenicity in humans despite favorable preclinical profiles. Competitive pressure from alternative strategies—cleavable linkers with higher bystander effect, higher DAR with stable site-specific conjugation, and emerging dual-warhead platforms—means the bar for clinical impact is not low. If early human data confirm improved tumor penetration without added toxicity, ADC design heuristics could shift toward functional, multi-payload architectures; until then, this remains a promising but unproven path that will demand careful biomarker planning and robust CMC underpinnings to move efficiently through development.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
