Abstract 3674: Pentarins: Improved tumor targeting through nanoparticle encapsulation of miniaturized biologic drug conjugates

Abstract

The specific targeting of cytotoxic drugs to solid tumors has achieved success with the advent of antibody drug conjugates (ADCs). This approach has had notable success but has also met with limitations. The most common issue limiting ADC effectiveness is believed to be low tumor permeation by these large (∼150 kDa) molecules. Attempts to address this limitation have been focused on the design of miniaturized biologic drug conjugates such as those with small protein or small molecule targeting moieties. However, these efforts uniformly result in conjugates with poor pharmacokinetics in contrast to the extended plasma pharmacokinetics observed with ADCs. The Pentarin platform encapsulates miniaturized biological drug conjugates within nanoparticles to improve the biodistribution of these classes of conjugates. There are multiple benefits to this strategy. Through the enhanced permeability and retention (EPR) effect the nanoparticles accumulate in the perivascular space of the tumor tissue. Next the nanoparticles release the permeable miniaturized conjugate that can penetrate in to the tumor, bind to an over-expressed target on the cancer cell surface, internalize the payload and elicit a strong biological effect. All of this is further enhanced by the extended plasma pharmacokinetics of the nanoparticle when compared to the conjugate alone. To exemplify the Pentarin platform we have designed novel miniaturized biologic drug conjugates to an over-expressed target found in small cell lung cancer. In vitro data has shown the designed conjugates specifically and potently target tumor cells expressing the receptor of interest. When encapsulated in nanoparticles, these miniaturized biologic drug conjugates have improved plasma pharmacokinetics, the amount of payload delivered to xenograft tumors is increased and the xenograft efficacy is significantly more pronounced over drug conjugate not in a nanoparticle. These observations correlate with in vivo mechanistic assays in the xenograft tissue. These data will be presented, together with the name of the target, to demonstrate the impact of the Pentarin platform and to show progress towards the first clinical candidate from this work. Citation Format: Mark T. Bilodeau, Rajesh Shinde, Brian White, Patrick Bazinet, Kerry Whalen, Michelle Dupont, Kristina Kriksciukaite, Jamie Quinn, Beata Sweryda-Krawiec, Rossitza Alargova, Adam Brockman, Patrick Lim Soo, Kristan Meetze, Benoit Moreau, Haley Oller, Mike Ramstack, Danielle Rockwood, Sukhjeet Singh, Tsun Au Yeung, Sudha Kadiyala, Craig Dunbar, Richard Wooster. Pentarins: Improved tumor targeting through nanoparticle encapsulation of miniaturized biologic drug conjugates. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3674. doi:10.1158/1538-7445.AM2015-3674

Cancer nanomedicine: progress, challenges and opportunities

“…Recently, an alternative novel multistage delivery strategy has been proposed to address the penetration problem 137 . Small-molecule drug conjugates (SMDCs) 138 and miniaturized biologic drug conjugates (mBDCs), including peptide–drug conjugates 139 , were developed to address the large size shortcoming of antibody–drug conjugates (ADCs), which limits their tumour tissue penetrability.…”

“…However, their considerable drawbacks include poor PK, which may limit their tumour exposure and therapeutic impact. By incorporating SMDCs and mBDCs into controlled-release polymeric NPs for multistep delivery to tumours, it may be possible to combine the superior PK and tumour accumulation of NPs with the deep penetration and specific tumour cell targeting of released SMDCs and mBDCs for optimal targeted cancer therapy 137 .…”

Rational nanocarrier design towards clinical translation of cancer nanotherapy

“…However, their poor PK may limit their exposure to tumor and treatment efficacy. Encapsulation of these conjugates into polymeric NPs may target the tumor targeting drug conjugates to tumor sites via EPR effects in controlled release manner for multiple steps tumor targeting, interstitial penetration and intracellular uptake to improve tumor therapy [107]. The similar concept of multistage delivery platforms has been used to encapsulate small-sized NPs such as 10 nm QDs into large particles such as hemispherical mesoporous silicon with 3.5 µm or 100 nm gelatin NPs to improve cancer treatment efficacy [98,108].…”

Factors Influencing the Delivery Efficiency of Cancer Nanomedicines

“…However, these combinations have drawbacks of poor pharmacokinetics, which decrease their efficiency. To overcome the problem, SMDCs and mBDCs are incorporated into controlled-release polymeric nanoparticles, to achieve good pharmacokinetics and tumor accumulation with higher tissue penetration (96)(97)(98).…”