Expanding the design space of protein-small… (R15GM151648) – Project Grant to The Trustees Of The Smith…

Abstract: Targeted therapy and targeted drug delivery have revolutionized clinical care of complex disease whenever these options are available - and, yet, only a minority of patients have access to these precision medicine approaches where their care is based on the molecular basis of their disease. Such molecular targeting leads to better patient outcomes and fewer toxic side effects compared to traditional treatment approaches, for a range of diseases. As part of expanding precision medicine to all patients with complex diseases, there is a critical need to meet the molecular targeting gaps in clinical care where such options currently do not exist. Protein- drug conjugates have immense promise in targeted therapy and drug delivery applications, with a number of recent successes in the form of antibody-drug conjugates (adcs) for cancer therapy. However, numerous design challenges for protein-drug conjugates remain, including narrow therapeutic windows and difficulty in translating success in oncology to other clinical indications. Even within oncology, solid tumors remain significantly more difficult to treat than hematological cancers. Our hypothesis is that the current set of modular components in the design space is limiting and leads to many of the current challenges. Therefore, there is an unmet need to create and validate protein-drug conjugate components and combinations beyond those currently being used. The overall goal of this proposed research is to expand the design space for protein-drug conjugates, enabling this class of molecules to have further success in a wider range of applications in biotechnology and medicine. We propose to validate scaffold proteins and side-chain reactive polymers as modular components for novel protein-drug conjugate structures. As a model protein scaffold for this work, we will use the FN3 polypeptide fold, which has been demonstrated to be extremely versatile for engineering molecular recognition using rational and directed evolution approaches. We propose to modify model FN3 proteins with canonical and non-canonical amino acids to enable site-specific bioconjugation reactions (aim 1). As a novel linker system for protein-drug conjugates, we propose to use side-chain reactive poly(pfpa), as a model polymer for synthesizing protein- polymer-drug conjugates. Side-chain reactive polymers are more chemically versatile than current linkers in use for adcs, and can serve multiple functions to overcome current ADC limitations. We will functionalize polymer poly(pfpa) to enable conjugation to specific protein sites, and load releasable small molecules onto the polymer, using a range of drug loading ratios, with combinations of small molecules to enable combination therapy (aim 2). We will measure and model cellular and tissue trafficking of the conjugates (aim 3), a key consideration for therapeutic success. The overall objective of this application is to extend the capacity of scaffold proteins and side-chain reactive polymers to fill the GAP in molecular targeting challenges. Our work will have a broader positive impact by establishing methods for synthesizing bioconjugates using a myriad of polypeptide folds and polymer linkers, towards the ultimate goal of creating targeted treatments for every patient who needs them.

Action	Obligated	Date
Amendment	$0	Aug 13, 2026
Original award	$398,833	Jul 18, 2023

Expanding the design space of protein-small molecule conjugates

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