# Designing Antibody Drug Conjugates for Durable and Complete Therapeutic Responses

> **NIH NIH R35** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $398,642

## Abstract

Abstract
After several decades of substantial investment in antibody drug conjugates (ADCs), the field has dramatically
expanded with the FDA approval of seven new agents in the past four years including five ADCs against solid
tumors. This recent success has reignited interest in the field, yet despite these approvals, fundamental
questions as to how these agents work in the clinic remain. One of the most important unanswered questions is
the role of the immune system in therapeutic responses to ADCs. This is a complex question given the multiple
ways in which ADCs can interact with the immune system. First, ADC payloads can drive immunogenic cell
death (ICD), which can stimulate immune cells via damage associated molecular patterns (DAMPs). Second,
the payloads can have direct effects on immune cells following bystander uptake of payloads or Fc-gamma
receptor mediated uptake. Finally, current ADCs in solid tumors use an IgG1 framework, where the antibodies
themselves are capable of Fc-effector functions that may also contribute to efficacy. The relative magnitude of
these effects is unknown, and until this question is answered, the most effective design of ADCs for cancer and
other diseases remains unclear. For example, these results determine what protein format will be most effective
and how different protein domains can be engineered to enhance efficacy. It also highlights what therapies will
synergize with ADCs to enhance a durable immune response. The long-term goal of this research is to
understand the fundamental properties of these complex drugs in sufficient detail to rationally combine the
antibody, linker, and payload with a particular target (in a select patient population) for maximum clinical efficacy
in both cancer and non-oncologic applications. The goal for this proposal is to quantify the relative contributions
of direct payload cell killing, indirect immune stimulation from ICD, and Fc-gamma receptor mediated signaling
and payload uptake in driving a strong immune response to ADC therapy in immunocompetent mouse models.
By using antibody ‘carrier’ doses in combination with ADCs and manipulating which species can bind Fc-gamma
receptors, these studies will dissect the relative contributions from each mechanism. Quantitative single-cell
pharmacokinetic measurements are also used to independently measure payload efficacy in cancer and immune
cell populations. The results are combined with hybrid agent-based computational models to rapidly simulate
thousands of permutations for predictive insight into the role of each mechanism in animal models and scaling
to the clinic. A graphical user interface can allow other scientists to make falsifiable predictions about their own
ADCs to guide the development of ADC therapeutics against any target of interest. These targets/payloads
include non-oncological applications, such as immunosuppressive ADCs and depletion of select cell populations
in the body. The successful completion of this w...

## Key facts

- **NIH application ID:** 10764864
- **Project number:** 2R35GM128819-06
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Greg Thurber
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $398,642
- **Award type:** 2
- **Project period:** 2018-08-01 → 2028-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10764864

## Citation

> US National Institutes of Health, RePORTER application 10764864, Designing Antibody Drug Conjugates for Durable and Complete Therapeutic Responses (2R35GM128819-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10764864. Licensed CC0.

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