# Pharmacokinetic strategies to increase monoclonal antibody uptake, distribution, and efficacy for treatment of solid tumors

> **NIH NIH R01** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2020 · $362,764

## Abstract

Although advances have been made in the treatment of cancer, therapy is inadequate for many patients, and it
is projected that there will be over 607,000 cancer deaths in the US in 2019. Many of these deaths will result
from cancers that develop as solid tumors, which are particularly difficult to treat with chemotherapy or with
biological drugs. Sub-optimal efficacy of anti-cancer monoclonal antibodies (mAb) and antibody-drug conjugates
(ADC) has been explained, in part, by poor uptake and distribution of these agents within solid tumors.
Pathophysiologic characteristics of solid tumors include their chaotic cellular growth, dense extracellular
matrices, poor and disorganized vascularization, decreased lymphangiogenesis, and high interstitial fluid
pressure. These characteristics limit the convective and diffusive transport of mAb and ADC within tumors,
leading to poor and heterogeneous intra-tumoral distribution. This proposal tests three new platform strategies
designed to improve the selectivity and efficacy of anti-cancer monoclonal antibody-based therapy by enhancing
the distribution of mAb and ADCs within solid tumors. Aim #1 introduces a novel strategy for overcoming the
“binding-site barrier” within tumors through transient inhibition of antibody binding to antigen, as achieved co-
administration of anti-idiotypic agents that allow short-term and reversible antagonism of mAb binding. Aim #2
will investigate the use of antibodies with pH-dependent, “catch-and-release” binding to bypass the catabolic
sink associated with receptor-mediated endocytosis of anti-cancer mAb. In Aim #3, targeted delivery of matrix-
modulating enzymes will be employed to achieve selective depletion of collagen in tumors, and to enable
improved intra-tumoral distribution of mAb and ADC. Each aim is strongly supported by mechanistic
mathematical modeling and by preliminary data demonstrating utility and feasibility. Pharmacokinetics, efficacy,
and safety of optimized anti-HER2 mAb and ADC therapy will be assessed using mouse models of HER2-
positive human cancer. The novel agents developed in this work may be suitable for immediate translation toward
optimization of trastuzumab and ado-trastuzumab emtansine treatment of HER2-positive breast and gastric
cancer patients. Additionally, the approaches introduced in this proposal may be extended for use in optimizing
therapy with all mAb and ADC applied to the treatment of solid tumors, potentially providing benefit to hundreds
of thousands of patients.

## Key facts

- **NIH application ID:** 10071254
- **Project number:** 1R01CA246785-01A1
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **Principal Investigator:** Joseph P Balthasar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $362,764
- **Award type:** 1
- **Project period:** 2020-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10071254

## Citation

> US National Institutes of Health, RePORTER application 10071254, Pharmacokinetic strategies to increase monoclonal antibody uptake, distribution, and efficacy for treatment of solid tumors (1R01CA246785-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10071254. Licensed CC0.

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