# Host Factors in Response to Therapeutic Monoclonal Antibodies and Vaccination

> **NIH NIH U01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2022 · $444,316

## Abstract

PROJECT SUMMARY. Effective responses in Fc-dependent, antibody-mediated killing for therapeutic ablation
require efficient and productive interactions between the cell-type specific Fc receptors of the host and the
therapeutic monoclonal antibody. The lack of effective responses in many patients, perhaps as much as 30%,
represents both an opportunity and a challenge to delineate the mechanistic basis for such differences.
Genetic inquiry can identify the contributions that the host brings to these differences. Our preliminary data
indicate that nearly one-third of persons have structural variants (SV) in the classical Fc locus in addition to the
prevalent single nucleotide polymorphisms affecting affinity of ligand binding, receptor mobility in the plane of
the cell membrane and quantitative receptor expression. These larger structural variants affect Fc receptors
on both lymphoid and myeloid cell series, and nearly a third of these variants are uncharacterized in terms of
genomic structure, resultant alterations in protein structure and impact on net biological function. New,
innovative technical approaches including linked-reads sequencing, now confirmed with conventional PCR,
have demonstrated novel structures in genomic organization. Application of CRISPR/Cas9 targeted excision
of the locus, coupled with linked-reads sequencing now enables resolution of novel structural variations
impacting biological function. Coupled with the potential to enhance expression of key activating receptors,
there is the exceptional opportunity to enhance both the host response to therapeutic mAbs but also to
vaccination protocols. Accordingly, the aims of this proposal are 1) enabled by our characterized cohort of
donors (N > 5,000) with different ancestral backgrounds, to characterize the genomic organization of novel
structural variants using linked-read, locus specific excision and long read strategies; 2) to identify the
predicted novel receptor proteins and their structures and assess their expression and function, including
possible decoy, signaling deficient structures; and 3) to develop a scalable, generalizable platform to assess
the repertoire of SNPs and larger genomic structural variants in the human FCGR genetic locus to understand
the population diversity in our expanding donor pool (>10,000) and assess the ability to predict response to
therapeutic antibody therapy. Assessment of the portfolio of receptors, their structures and their expression
will enable strategies for selection and stratification of recipients for an optimal precision medicine approach.

## Key facts

- **NIH application ID:** 10348654
- **Project number:** 5U01AI148108-03
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Robert P. Kimberly
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $444,316
- **Award type:** 5
- **Project period:** 2020-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10348654

## Citation

> US National Institutes of Health, RePORTER application 10348654, Host Factors in Response to Therapeutic Monoclonal Antibodies and Vaccination (5U01AI148108-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10348654. Licensed CC0.

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