Abstract 1734: Encapsulating therapeutic antibodies for tumor specific activation and delivery using a clinically validated pH-sensitive nanoparticle platform

Abstract

Background: Though antibodies for cancer treatment have achieved clinical and commercial success over the past few decades, a large portion are limited by suboptimal efficacy and on-target off-tumor toxicity due to ubiquitous expression of their targets. A plethora of molecular engineering approaches have been introduced to restrict the activity of antibodies solely to tumor instead of healthy tissue with the goal of improving the therapeutic index, such as masking the binding sites of antibodies with inhibitory domains. However, sophisticated modification is usually required while the outcomes are often mediocre. Previously we developed an ultra-pH sensitive nanoparticle platform named ON-BOARD. The strength of this technology stems from its ability to preferentially release the payload specifically in the acidic tumor microenvironment while staying intact in normal tissue. The safety and feasibility of using such a platform have been demonstrated by successful delivery of fluorophore to tumors for imaging of multiple tumor types in Phase I and II clinical trials with Pegsitacianine (formerly “ONM-100”). Pegsitacianine has been shown to be generally well-tolerated with an infusion-related reaction as the most common adverse event in the clinical trials conducted to date. Based on the clinical results, we present the ON-BOARD platform herein as a potential universal and effective tool for tumor specific activation and delivery of therapeutic antibodies without the need for sophisticated antibody chemistry or engineering. Methods: Biosimilar monoclonal antibodies of atezolizumab, cetuximab, pembrolizumab, trastuzumab, and ipilimumab with the same variable region sequences as the original pharmaceutical drugs were used to demonstrate encapsulation by the ON-BOARD platform and pH-dependent activation. Encapsulated antibodies were purified using SEC and the encapsulation efficiencies were quantified by HPLC. Particle size and uniformity were studied by DLS. The formulations were accessed for bioactivity in vitro under neutral pH or acidified conditions using appropriate cell-based reporter assays. Results: ON-BOARD nanoparticles successfully encapsulated the antibodies mentioned above without additional modification of the original antibody. Encapsulation efficiency ranged from 50-100%. The formulations were characterized as uniformly distributed particles < 100nm in size with good stability. In vitro assessment by cell-based reporter assays demonstrated > 100-fold activation window between the acid-activated and intact formulations. The pH-dependent activation was further confirmed by affinity and binding assay. Conclusions: The ON-BOARD pH-sensitive nanoparticle platform demonstrated potential as an effective and universal tool for tumor specific activation and delivery of antibody-based therapeutics. Citation Format: Gaurav Bharadwaj, Qingtai Su, Stephen Gutowski, Curran Parpia, Ashley Campbell, Jason Miller, Tian Zhao. Encapsulating therapeutic antibodies for tumor specific activation and delivery using a clinically validated pH-sensitive nanoparticle platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1734.

1200 A clinically validated pH-sensitive nanomedicine platform for encapsulating therapeutic bispecific T cell engagers for tumor specific delivery and activation

“…5 To minimize the off-tumor effects, we have developed ON-BOARD, an ultra-pH sensitive nanoparticle platform, has shown utility in cytokine and monoclonal antibody encapsulation and targeted delivery to the acidic tumor microenvironment. 6,7 The clinical safety and feasibility of ON-BOARD has been demonstrated by effective delivery of fluorophores to solid tumors for imaging of multiple tumor types in Phase I and II clinical trials with pegsitacianine. 8 Herein we expand the utility of ON-BOARD platform for the encapsulation and pH-specific activation of bispecific antibodies with potential for anticancer therapy.…”

1329 Ultra-pH sensitive nanoparticles increase therapeutic index of IL-2-Fc

“…We developed ON-BOARD, an ultra-pH sensitive nanoparticle technology for tumor-targeted delivery of drug payloads, including biologics to acidic tumor microenvironment (TME). 2,3 The clinical safety and feasibility of ON-BOARD has been demonstrated by the effective delivery of fluorophores to solid tumors for imaging of multiple cancer types in Phase I/II clinical trials by pegsitacianine. 4 Herein we report ONM-405, an ON-BOARD-encapsulated IL-2-Fc, which is designed to mask toxicity in normal tissues after systemic administration, while achieving pH-activable release of IL-2-Fc at the tumor site against solid cancers.…”