Abstract P4-21-18: Pre-clinical antitumor activity, tumor localization, and pharmacokinetics of MP0274, an apoptosis inducing, biparatopic HER2-targeting DARPin®

Abstract

Abstract Background: HER2 positivity is an important predictive factor for treatment with anti-HER2 agents in several cancers. However, currently available monoclonal antibody and tyrosine kinase inhibitor drugs rarely achieve full disease control. We have developed a new HER2-targeting molecule with a unique pro-apoptotic mode of action that may provide additional benefit to patients. The DARPin® MP0274* binds to two distinct non-overlapping HER2 epitopes and to human serum albumin for half-life extension. As previously shown**, in vitro, MP0274 induces apoptosis and inhibits proliferation of cells expressing HER2 (IHC3+, IHC2+ and IHC1+) and potently inhibits HER2/HER3 downstream signaling. To support clinical development of MP0274, we tested the potency of MP0274 in several HER2 expressing patient-derived xenograft (PDX) models and investigated tumor localization. In addition, pharmacokinetics (PK) analysis was performed in cynomolgus monkeys. Methods: Antitumor activity of MP0274 was tested in breast and gastric HER2 expressing PDX mouse models and was compared to standard of care therapies. Tumor localization of MP0274 was studied using an Indium-111 labeled version of MP0274 in a human ovarian adenocarcinoma (SKOV-3) xenograft model by whole-body SPECT/CT imaging. The PK of MP0274 was studied in cynomolgus monkeys (MP0274 is cross-reactive with cynomolgus HER2). Results: In breast and gastric cancer PDX models, MP0274 showed superior efficacy compared to trastuzumab and lapatinib and equivalent efficacy compared to trastuzumab plus pertuzumab as measured by relative tumor volume. The imaging study with SPECT/CT demonstrated that MP0274 localizes effectively to the HER2-expressing human tumor within 24 h. The PK study in cynomolgus monkeys showed a half-life of ≥5 days at doses of 5 and 10 mg/kg while at the lowest dose tested (1 mg/kg) MP0274 had a terminal half-life of 0.4 days. The PK results are indicative of target-mediated clearance that becomes saturated at doses above 1 mg/kg. Conclusions: MP0274, with its unique pro-apoptotic mode of action, demonstrates excellent activity in preclinical PDX models, fast localization to tumor and a long half-life in cynomolgus monkeys. MP0274 was well tolerated in all studies. These results suggest that MP0274 has the potential to provide additional clinical benefit to patients with HER2-expressing tumors. A GLP repeated dose toxicology study is ongoing and a phase I clinical trial is in preparation. * DARPins are small repeat proteins, designed to bind targets with high affinity and specificity, which can be combined in a modular fashion to produce multi-functional agents. ** U. Fiedler et al. SABC 2013. Abstract# 1094 & Poster# P4-12-30. Citation Format: Fiedler U, Metz C, Zitt C, Bessey R, Béhé M, Blanc A, Schibli R, Dolado I, Herbst J, Dawson KM, Kiemle-Kallee J. Pre-clinical antitumor activity, tumor localization, and pharmacokinetics of MP0274, an apoptosis inducing, biparatopic HER2-targeting DARPin® [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-18.