Abstract Background: Nectin-4 is an attractive tumor-associated antigen, with over-expression in various solid tumors including UC, TNBC, CC, NSCLC, and HNSCC, while minimal expression in normal tissues. High Nectin-4 expression is closely associated with tumor development and poor prognosis, acting as a crucial biomarker for cancer recurrence and metastasis. Currently, only one Nectin-4 ADC with MMAE as the payload, Enfortumab Vedotin (EV), has been approved for marketing. However,EV has the issue of non-uniform DAR values, which can result in drug heterogeneity. Moreover, there is a black box warning in its instruction for severe and fatal skin adverse reactions. Therefore, we developed a novel Nectin-4-targeted ADC drug with a new mechanism, LNF2105 whose homogenous drug-antibody ratio and novel linker chemistry increase the stability of the conjugate in the systemic circulation, enabling highly efficient drug delivery and avoiding off-target toxicity. Methods: To measure the bystander killing effect, CHO-GFP and MCF-7 cell lines were used. To assess serum stability, LNF2105 and DS8201 were incubated at 37°C for up to 25 days in human plasma; free DXD was quantified by LC/MS-MS. For in vitro studies, assays for competitive ability and specificity, binding affinity, internalization, ADCC activity, and killing activity were performed. The in vivo antitumor efficacy of LNF2105 was evaluated in MDA-MB-468, xPC3, NCI-H322, and SW780 in subcutaneous xenograft models.PK properties were studied in cynomolgus monkeys, and safety studies of the payload and ADC were conducted in rats and cynomolgus monkeys, respectively. In general toxicology studies, cynomolgus monkeys and ICR mice were used. Results: LNF2105 appeared as a homogeneous ADC composed of a Nectin-4-targeting monoclonal antibody conjugated to a Topo I inhibitor using interchain-disulfide-based site-specific conjugation technology, with DAR 8. A significant bystander killing effect were observed. Compared to DS8201, the payload dropout rate of LNF2105 was much slower and its plasma stability was higher. In various solid tumor xenograft models, LNF2105 demonstrated dose-dependent tumor suppression, with efficacy comparable to or superior to that of EV, which may be attributed to the site-specific conjugation. In addition, LNF2105 demonstrated a favorable safety profile, and the only side effect on the skin of monkeys was reversible. Ocular, pulmonary, and hematologic toxic side effects—common in Nectin-4-targeted therapy—were not observed. The HNSTD in monkey was 6 mg/kg, with milder adverse events compared with those of EV. Conclusions: Overall, LNF2105 is a Nectin-4-directed ADC drug with a specially designed linker and a DXD analogue payload. Next generation site-specific conjugation technologies endow the drug with excellent homogeneity, remarkable preclinical antitumor activity, and a favorable safety profile. Citation Format: Zhongsong Zhu, Shili Wang, Jinhua Xu, Fanliang Cheng, Yuqiang Zhu, Peibiao Zhang, Guimin Zhang, Lili Zhao, Zhenyu Li. LNF2105, a next-generation nectin-4-targeted ADC with a specially designed linker and a DXD analogue abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4432.
Zhu et al. (Fri,) studied this question.