Abstract C184: BIND-510 improves the pharmacokinetics, tolerability, tumor accumulation and tumor growth inhibition in preclinical models of cancer compared to vincristine sulfate
Authors: Cadzow Louise , Arnold Kristen , Thrasher Daniel , Nolan James , Horhota Allen , Lewis-Clark Eric , Wright James , Low Susan 
Published: May 2016

Background: BIND-510 is a novel, prostate-specific membrane antigen (PSMA) targeted Accurin polymeric nanoparticle encapsulating vincristine (VCR). PSMA is expressed on prostate cancer cells and on vasculature of many solid tumor types. VCR is an anti-mitotic agent most commonly used in the treatment of hematological cancers. Accurins have shown promise for targeting oncology agents preferentially to tumors, while limiting systemic exposure. To determine the potential benefit of encapsulation of VCR, BIND-510 was evaluated in pharmacokinetic (PK), tolerability, tumor accumulation and anti-tumor activity studies compared to VCR. The advantage of active targeting to enhance anti-tumor activity of BIND-510 was also explored in a PSMA expressing xenograft model. Immunohistochemistry was also performed to evaluate PSMA expression in hematological cancers.

Methods: VCR was encapsulated into nanoparticles using a nanoemulsion process to produce BIND-510. Single intravenous doses of BIND-510 were administered to rats for evaluation of PK. Tumor accumulation, tolerability and anti-tumor activity studies were performed in athymic mice implanted with breast cancer (MX-1), non-small cell lung cancer (NCI-H460), nasopharyngeal carcinoma (KB), PSMA-expressing prostate cancer (C4-2) and Burkitt's lymphoma (Ramos) xenografts. PSMA immunohistochemistry was also performed in lymphoma and bone marrow tumor microarrays (TMA) to evaluate PSMA expression in hematological cancers.

Results: BIND-510 has a markedly different PK profile compared to VCR with increased exposure (300-fold) and decreased volume of distribution (500-fold) and clearance (300-fold). BIND-510 accumulated in KB tumors at an 8-fold higher concentration than VCR, and was shown to be more tolerable than VCR. BIND-510 administered to mice with KB xenografts as a single dose at the maximum tolerated dose (MTD) for VCR (1.5 mg/kg) resulted in a longer tumor growth delay compared to VCR. Due to improved tolerability, BIND-510 could be administered at a dose of 3 mg/kg, resulting in complete responses in some mice, and even longer tumor growth delay than VCR or BIND-510 dosed at 1.5 mg/kg. Similar tolerability and anti-tumor activity data were obtained in MX-1 and Ramos xenografts. PSMA targeting of BIND-510 in C4-2 tumor xenografts resulted in a tumor growth inhibition (TGI) of (79%) compared to non-targeted VCR nanoparticles which caused a 47% TGI at the same VCR dose level. NCI-H460 tumor xenografts are insensitive to VCR at MTD, but are sensitive to BIND-510 due to improved tolerability at higher dose levels. PSMA immunostaining was detected in the neovasculature of 27.5% diffuse large B cell lymphoma tumors and 35% of multiple lymphoma tumors analyzed.

Conclusions: BIND-510 exhibits differentiated PK, tumor accumulation, tolerability and anti-tumor activity compared to VCR. In combination with the demonstration of PSMA expression in hematological cancers, our findings support the feasibility of developing BIND-510 as a targeted clinical therapy with the potential benefit of reduced toxicity and improved anti-tumor activity compared to currently available treatments in hematological as well as solid tumor settings.

Citation Format: Louise Cadzow, Kristen Arnold, Daniel Thrasher, James Nolan, Allen Horhota, Eric Lewis-Clark, James Wright, Susan Low. BIND-510 improves the pharmacokinetics, tolerability, tumor accumulation and tumor growth inhibition in preclinical models of cancer compared to vincristine sulfate. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C184.