# Small Animals Core

> **NIH NIH P01** · DUKE UNIVERSITY · 2021 · $250,000

## Abstract

Abstract - Small Animal Models Core
 The objective of the Small Animals Model Core is to generate a series of mouse models that express
the unmutated common ancestor (UCA) or intermediate antibodies (IAs) of the DH511 lineage of broadly
neutralizing antibody (bnAb). These mouse models will be used to test the efficacy of immunogens that are
designed to elicit the DH511 lineage of bnAbs. Toward this end, the Animal Model Core will generate two types
of mouse models. The first type of model expresses pre-rearranged V(D)J exons of the DH511 antibodies.
Owing to allelic exclusion, the pre-rearranged DH511 V(D)J exon will inhibit the rearrangement of endogenous
mouse immunoglobulin (Ig) loci. As a result, B cells in these mice will express predominantly DH511
antibodies. One common problem for this type of mouse model is that tolerance control mechanisms delete B
cells expressing the knock-in human Ig genes. To overcome this hurdle, we have developed a method to
express human antibodies conditionally in mature B cells, thereby circumventing tolerance control during B cell
maturation. If necessary, we will employ this conditional expression system to generate DH511 mouse models.
Since this type of model provides a large population of B cells expressing DH511UCA or IAs, it would serve as
a sensitive assay for the initial evaluation of immunogens. However, the system does not recapitulate the
complexity of physiological B cell repertoire in at least two major respects. First, the unique UCA expressed in
the mouse model may not be present in a fraction of human populations. Second, the system lacks competing
antibodies for irrelevant epitopes. To address these limitations, the Animal Model Core will generate a second
type of mouse model where the VH3-15, D3-3 and JH6 gene segments of DH511 undergo de novo V(D)J
recombination. Due to junctional diversity, the recombination will create a wide range of CDR H3s, some of
which may be suitable for the development of DH511-like antibodies. Moreover, the system does not preclude
the rearrangements of endogenous mouse Ig gene segments. Therefore, the B cell repertoire of this mouse
model will consist of potential DH511 precursors as well as other human VH3-15/D3-3/JH6 and mouse
antibodies. Immunization of this mouse model could assess the ability of the immunogen to select for and
mature DH511 precursors in the context of complex antibody repertoires.

## Key facts

- **NIH application ID:** 10132976
- **Project number:** 5P01AI138211-03
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** S. Munir ALAM
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $250,000
- **Award type:** 5
- **Project period:** 2019-04-09 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10132976

## Citation

> US National Institutes of Health, RePORTER application 10132976, Small Animals Core (5P01AI138211-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10132976. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*