Abstract P5-16-16: A novel investigational nanoparticle therapeutic (DAN-222) for breast cancer and other solid tumors

Abstract

Abstract Background: Here we introduce a novel nanoparticle therapeutic, DAN-222, which offers a variety of potential clinical benefits in delivery of chemotherapy versus native drug, including a broader therapeutic index. DAN-222 is a polymeric nanoparticle covalently conjugated with camptothecin (CPT), a topoisomerase I inhibitor, that demonstrates enhanced efficacy over native CPT at the same dose and has significantly reduced bone marrow exposure (limiting potential safety concerns), thus widening the therapeutic index with respect to both efficacy and safety. The nanoparticle therapeutic provides sustained drug exposure through conjugation of the chemotherapy payload to the novel biocompatible polymer scaffold that can be modulated by choice of linker, allowing for optimization of the release rate for a given payload and target. To illustrate the flexibility and capabilities of modulating payload release kinetics, we present a series of CPT-containing nanoparticles with different linkers encompassing a wide range of in vitro release rates. We also demonstrate the vastly enhanced efficacy of DAN-222 in multiple breast cancer xenograft mouse models. Methods: In vitro release: Release of CPT from nanoparticles formed with various linkers was evaluated by HPLC in pH 5.5 PBS (endosomal pH), pH 7.4 PBS (physiologic pH), mouse plasma, and human plasma. Efficacy: Breast cancer xenograft tumor models with human BT-474 and MDA-MB-231 were propagated in CB.17 SCID and NCr nu/nu mice respectively, with 10 animals per group. Results: All linkers demonstrate linear kinetics and release slowly at reduced pH, consistent with the mechanism of release. At physiologic pH, a diversity of in vitro release rates is achieved by modulating the sensitivity of the linker. Importantly, all linkers have similar release in mouse and human plasma, indicating strong cross-species translation. Results in the mouse xenograft models showed that DAN-222 had a superior and sustained efficacy compared to CPT and irinotecan (an approved topoisomerase-1 inhibitor) as demonstrated by tumor growth inhibition. Conclusions: We demonstrate the ability to modulate the payload release kinetics from the nanoparticle therapeutic by the choice of linker, with species-independent release rates. With an optimal linker selected, DAN-222 shows enhanced and sustained efficacy over native CPT. Since DAN-222 has previously been shown to have reduced bone marrow exposure of chemotherapy, it may provide a significant therapeutic advancement with a wider therapeutic index based on both enhanced efficacy and improved safety. DAN-222 is advancing to a clinical trial in HER2-negative metastatic breast cancer. In vitro release half-lives (t1/2) (hours)Linker 1Linker 2Linker 3Linker 4Linker 5PBS, pH 5.5>50>50>50>50>50PBS, pH 7.47.120.5>50>50>50Mouse Plasma1.74.817.237.7>50Human Plasma1.64.817.137.8>50 TreatmentBT-474MDA-MB-231Day 25 TGI(%)Day 36 TGI*(%)Day 25 TGI (%)Day 32 TGI* (%)Camptothecin (3 mg/kg)64404756Irinotecan (100 mg/kg)71594751DAN-222 (3 mg/kg CPT)93967475*Day the vehicle control group reached the study endpoint. Citation Format: Emily A Wyatt, Ashley P Wright, Carl M Blumenfeld, Robert J Lamm, Timothy Hagerty. A novel investigational nanoparticle therapeutic (DAN-222) for breast cancer and other solid tumors [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-16-16.