Sbir phase i: antibody brush polymer conjugates with high drug antibody ratios and immunostimulatory payloads for treatment of late-stage cancers

This $256,000 National Science Foundation project grant supports the development of novel antibody-brush polymer conjugates with high drug-to-antibody ratios by Window Therapeutics, Inc. The goal is to create the next generation of antibody-drug conjugates for cancer immunotherapy through research and development of antibody-brush polymer conjugates that can load up to 100 drugs per antibody. These conjugates aim to enable immunotherapies to treat immunoresistant cancers like colorectal cancer by allowing use of immunostimulatory payloads with narrow therapeutic windows. Specifically, the company will create libraries of conjugates loaded with toll-like receptor and STING agonists shown to have preclinical promise but clinical development challenges due to limited targetability and dosing. The project will evaluate optimized conjugates for tolerability, pharmacokinetics, biodistribution, efficacy, and curative potential in colorectal cancer models. Funded through the National Science Foundation's Engineering Directorate under the CFDA 47.041 program, this March 1, 2022 project grant aims to advance the novel immunotherapy technology into clinical applications.

Abstract

The broader impact/commercial potential of this small business innovation research (sbir) phase i project is to make a new class of antibody-based immunotherapies that can be generally applicable to oncology patients. For select cancer patients, immunotherapies can serve as a cure by reactivating their natural immune systems to fight against their cancers. Unfortunately, cancers are often mutated to evade the small library of currently approved immunotherapies. Many promising experimental small molecule immunotherapies cannot be used because they cannot effectively accumulate in cancer sites at high enough concentrations and often cause severe side effects through off-target damage to healthy organs. Antibodies can be used to help shuttle drugs directly to cancer sites but are currently limited. This project advances a novel technology that increases antibody drug loading over an order of magnitude, up to 100 drugs per antibody. These novel antibody brush polymer conjugates (abcs) will enable immunotherapies to treat notoriously immunotherapy resistant cancers, such as colorectal cancer. This small business innovation research (sbir) phase i project will create the next-generation of antibody-drug conjugate (ADC) immunotherapies through the research and development of antibody-brush polymer conjugates (abcs). Due to limited chemical handles, adcs have low drug loadings that force the use of cytotoxic drug payloads like auristatins that cause severe adverse events in patients. This project will develop conjugation techniques that will lead to abcs with drug-antibody ratios as high as 100. Brush polymers, through a combination of peg shielding and targeted drug release, enable this higher drug loading that will lead to both greater efficacy against low expression antigen targets in cancer and application of drugs with more diverse mechanisms of action. Specifically, this project will create libraries of abcs loaded with immunostimulating molecules like TLR and sting agonists that, despite significant preclinical promise, have stagnated in clinical development due to narrow therapeutic windows and limited targetability. Optimized immunostimulatory abcs will be evaluated in vivo for tolerability, pharmacokinetics, biodistribution, efficacy, and curative potential in traditionally immunotherapy-resistant colorectal cancer animal models. This sbir phase i research will enable further development of the novel immunotherapies into clinical applications. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the foundation's intellectual merit and broader impacts review criteria.