Targeting NaPi2b in NSCLC: Unveiling the Potential of XMT-1536, a Potent ADC in Xenograft Models

The research abstract discusses XMT-1536, a new and potent antibody-drug conjugate (ADC), which targets the type II sodium-dependent potassium transporter NaPi2b (SLC34A2). This protein is particularly prevalent in non-squamous non-small cell lung cancer (NSCLC) and non-mucinous ovarian cancer (OC), with limited expression in normal tissues, making it a promising target for ADC therapy.

XMT-1536 is composed of the XMT-1535 antibody, which is humanized and specifically binds to NaPi2b, and an average of 15 auristatin molecules. The Dolaflexin ADC platform is used to conjugate the antibody with the drug payload. The auristatin is designed to be enzymatically cleaved once the ADC reaches the endosome/lysosome compartment of the target cells, releasing a cytotoxic derivative that can also kill neighboring cells through a bystander effect.

In vitro studies have shown that XMT-1535 has a high affinity for OC cells, and this binding is not affected by the conjugation process. XMT-1536 has demonstrated significant cytotoxic potency against OC and NSCLC cell lines, with IC50 values in the picomolar range, and is considerably more potent than a non-binding control ADC.

In vivo experiments using mouse xenograft models of OC and NSCLC have yielded positive results. In the OVCAR3 OC model, single and multiple doses of XMT-1536 led to partial and complete tumor regressions, respectively. In a patient-derived model of KRAS mutant NSCLC, the treatment also resulted in tumor growth delay and regressions.

XMT-1535's cross-reactivity with cynomolgous monkey NaPi2b has allowed for the evaluation of XMT-1536's tolerability in non-human primates. In a single dose study, the compound showed no target-mediated toxicity and limited adverse effects, notably without bone marrow toxicity, which is a common issue with cleavable auristatin ADCs.

Based on these promising preclinical results, XMT-1536 is progressing towards early clinical development with the aim of treating tumors that express NaPi2b. The abstract concludes with a citation to the study's presentation at the 107th Annual Meeting of the American Association for Cancer Research.