Background: Phase 3 clinical results demonstrate that nab-paclitaxel (ABX) exhibits single agent activity in patients with metastatic melanoma relative to dacarbazine. Additionally, phase 2 clinical data suggest that ABX combined with bevacizumab (BEV) with/without carboplatin exhibits greater clinical efficacy than ABX alone. We hypothesized that the latter may be due to a pharmacokinetic, non-covalent interaction between bevacizumab (BEV) and nab-paclitaxel (ABX) allowing for greater localization of ABX to sites of VEGF overproduction (metastases). Herein we present pre-clinical data describing the utility of experimentally created ABX/BEV complex nanoparticles used to deliver ABX to VEGF producing cancer targets.
Methods and Results: To test whether BEV binds to ABX we employed flow cytometry and discovered that the BEV does bind to ABX while preserving the ability of BEV to bind its ligand, VEGF. To measure binding affinity we used Biolayer Interferometry (BLItz) to measure association and dissociation constants. Results of BLItz experiments demonstrate that the binding affinity of BEV to ABX is pH and temperature dependent. The size and stability of the nanoparticle formed by binding BEV and ABX was determined using light refraction (Mastersizer) and Brownian motion (Nanosight). Results of these experiments suggest that a range of nanoparticles can be produced and stability of the BEV particle is increased relative to ABX particles alone. Finally the tumor efficacy of the BEV/ABX complex relative to ABX and BEV as well as sequential administration of the two drugs was tested in a xenograft model of A375 human melanoma cell line. Pharmacokinetic studies in these mice suggest that more ABX is deposited in the tumor site when treated with the complexes relative to ABX alone.
Conclusions: The therapeutic antibody BEV has the capability to bind to the chemotherapy drug ABX while still binding its ligand, VEGF. The resulting nanoparticle is more stable than the original ABX particle. In a preclinical model of human A375 xenografts in nude mice, AB160 treatment offers significantly improved antitumor activity beyond that of ABX, BEV or ABX+BEV with no additional toxicity. Initial results indicate that the improved efficacy of the ABX/BEV nanoparticle relative to ABX alone is primarily due to the ability of the anti-VEGF antibody (BEV) to target the chemotherapy agent to the tumor where local VEGF concentration is very high. Clinical translation of the safety of a 160nm AB particle (AB160) in patients with metastatic melanoma is in progress.
Citation Format: Wendy K. Nevala, Svetomir N. Markovic. Targeted nano-immune conjugates to melanoma: Preclinical testing of bevacizumab targeted nab-paclitaxel. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B77.
- ©2015 American Association for Cancer Research.