# Optimizing antibody-based therapy through a system platform of pharmacokinetics-pharmacodynamics-immunodynamics

> **NIH NIH R35** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $370,335

## Abstract

PROJECT SUMMARY/ ABSTRACT
Therapeutic antibodies have achieved great success in a variety of diseases such as autoimmune disorders
and cancers; however, their therapeutic potential has not been fully realized yet. Many FDA-approved
antibodies now face high therapeutic hurdles, such as inadequate efficacy in monotherapy and high rates of
resistance. Some hurdles can be overcome by engineering new antibody entities with either improved target
selectivity or functionality. Many others remain unresolved, as they are not just about the antibody itself, rather
essentially as a result of antibody discordant interactions with the host system. For instance, CD20-targeted
antibodies often confront resistance that is due to overwhelming antibody exposure to the immune system
leading to exhausted effector function and then loss of drug sensitivity. To resolve those issues, we plan to
develop a system platform that collectively consolidates the fundamental properties of the antibody
and the host system, and integrate their spatial/temporal coordination. If it is established, this platform
will alleviate or even sidestep these therapeutic hurdles and facilitate efforts to optimize the current
antibody-based therapies. We will develop this system platform on multiple scales from cells to the whole
body, by collectively evaluating all steps of antibody actions from dosing to final responses. Specifically, we will
collaborate with experts in the fields of radiology and molecular imaging to develop novel labeling approaches
to track antibody entities at multiple levels (i.e., blood, tissue, interstitial fluid, and cell) and assess antibody
system persistence and distribution to the site(s)-of-action (pharmacokinetics) (Project 1). We will apply a
series of combined experimental and computational approaches to assess the temporal and spatial antibody-
antigen interactions in vivo, and the subsequent cellular and subcellular events (Project 2). Advanced cell-
labeling methods will be applied to monitor lymphocyte migration, infiltration, functional orientation, and
dynamics of effector function (e.g., FcγR) and the complement system (e.g., C3 and C4) in the tumor
microenvironment. Patient-derived blood and solid tumors will be used to prepare lymphocytes, on which
dynamics of effector function will be assessed. This will better mimic the tumor environment and increase our
ability to predict patient responses. Antibody therapy will be further tailored to coordinate the status of immune
system and the dynamics of effector function for maximal effect (Project 3). All these quantitative studies
will support this system platform to facilitate the proper selection of an antibody, determine the precise
dose and dosing interval to attain the desired target exposure and target engagement. The time course
of target binding will coordinate physiology and dynamics of the immune system to achieve optimal
treatment.

## Key facts

- **NIH application ID:** 9963279
- **Project number:** 5R35GM119661-05
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Yanguang Cao
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $370,335
- **Award type:** 5
- **Project period:** 2016-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963279

## Citation

> US National Institutes of Health, RePORTER application 9963279, Optimizing antibody-based therapy through a system platform of pharmacokinetics-pharmacodynamics-immunodynamics (5R35GM119661-05). Retrieved via AI Analytics 2026-07-09 from https://api.ai-analytics.org/grant/nih/9963279. Licensed CC0.

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