Discovery And Preclinical Development Of A Highly Potent Napi2b-Targeted Antibody -Drug Conjugate (Adc) With Significant Activity In Patient -Derived Non -Small Cell Lung Cancer (Nsclc) Xenograft Models

The type II sodium-dependent potassium transporter NaPi2b (SLC34A2) is highly expressed in non-squamous NSCLC and non-mucinous ovarian cancer (OC) with restricted normal tissue expression, suggesting it may be a suitable ADC target for these indications. XMT-1536 is a novel, highly potent anti-NaPi2b ADC comprised of an average of 15 auristatin molecules conjugated to XMT-1535, a novel humanized anti-NaPi2b antibody, via the Dolaflexin ADC platform. The auristatin payload is enzymatically cleaved upon ADC trafficking to the endosome/lysosome compartment, releasing a cytotoxic auristatin derivative that is capable of bystander effect killing. In cell binding assays, XMT-1535 antibody binds to OC cells with low nanomolar affinity, which is unaffected by conjugation of the Dolaflexin drug conjugate. In vitro cytotoxicity assays show picomolar potency of XMT-1536 in OVCAR3 (OC; 32,000 NaPi2b molecules/cell; IC50 2 pM), TOV21G (OC; 10,000 NaPi2b molecules/cell; IC50 40 pM), and HCC-4006 (NSCLC; 52,000 NaPi2b molecules/cell; IC50 130 pM). In each cell line, XMT-1536 is 1-2 logs more potent than a non-binding Dolaflexin ADC control, consistent with target-dependent cytotoxic effect. XMT-1536 was tested in mouse xenograft models of OC and NSCLC. In the OVCAR3 OC model, XMT-1536 induced partial tumor regressions after a single dose of 3 mg/kg (0.21 mg/kg payload equivalent dose), and complete tumor regressions after a single dose of 5 mg/kg (0.36 mg/kg payload dose) or 3 weekly doses of 3 mg/kg. In contrast, a non-binding Dolaflexin ADC with comparable drug loading was inactive after 3 weekly administrations of 3 mg/kg, consistent with the anti-tumor activity of XMT-1536 being mediated through binding to the NaPi2b target. XMT-1536 was also tested in a patient-derived model of KRAS mutant NSCLC, where 3 weekly doses of 3 mg/kg led to significant tumor growth delay and regressions in some animals. Evaluation of XMT-1536 in additional patient derived xenograft models is on-going and will be updated at the meeting. XMT-1535 is cross-reactive with cynomolgous monkey NaPi2b, allowing an informative evaluation of whether XMT-1536 retains good tolerability in non-human primate. XMT-1536 was administered to cynomolgous monkeys in an exploratory single dose study up to 5 mg/kg ADC (4294 μg/m2 auristatin payload equivalents), with no observed target-mediated toxicity and limited adverse findings. Of note, there was no evidence of bone marrow toxicity, which has been observed generally for cleavable auristatin ADCs, and specifically for a recently published auristatin-based NaPi2b ADC (Lin et al., Clinical Cancer Research, 2015). Based on these data XMT-1536 is advancing to early clinical development for the treatment of NaPi2b-expressing tumors. Citation Format: Natalya Bodyak, Alex Yurkovetskiy, Mao Yin, Dmitry Gumerov, Reddy Bollu, Patrick Conlon, Venu R. Gurijala, Dennis McGillicuddy, Cheri Stevenson, Elena Ter-Ovanesyan, Peter U. Park, Laura Poling, Winnie Lee, Michael DeVit, Dongmei Xiao, LiuLiang Qin, Timothy B. Lowinger, Donald A. Bergstrom. Discovery and preclinical development of a highly potent NaPi2b-targeted antibody-drug conjugate (ADC) with significant activity in patient-derived non-small cell lung cancer (NSCLC) xenograft models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1194.