# Immunogen Design for Specific BCR Activation

> **NIH NIH U19** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2020 · $1,997,824

## Abstract

For the past three decades intense efforts by numerous investigators aimed at the design of immunogens 
that would stimulate the production of broadly neutralizing antibodies (bnAbs). Although improvements were 
made in the design/engineering, expression and purification of Env-based, in general the neutralizing 
antibody responses elicited by such immunogens are narrow in breadth and potency. One of the known 
targets of bnAbs is the CD4-BS of the HIV Env. Regarding the inability of recombinant Envs to elicit anti- 
CD4-BS, our studies suggest that one reason for this is that Env immunogens do not engage the germline 
forms of known anti-CD4-BS bnAbs and of the corresponding germline B cell receptors (BCRs). We believe 
that a direct consequence of this lack of Env-BCR reactivity is that the process of production of such 
antibodies is not initiated by such Env immunogens. Our proposed studies are based on our recent design 
of a trimeric gp140 clade C Env protein that engages the germline VRCOI and NIH45-46 antibodies (two of 
the most potent and broadly neutralizing anti-CD4-BS antibodies known) and activate B cells that express 
the corresponding BCR forms of these antibodies. We believe, therefore, that we identified a way to 
overcome the earliest roadblock in the elicitation of such bNAbs. As such, our findings are very novel and 
highly significant to efforts to develop by immunization bNAbs against HIV. In this Project One, we propose 
to further optimize our immunogens to improve their ability to engage and activate the germline BCRs of 
known anti-CD4-BS bNAbs. This Project One has three Specific Aims: 1) Optimize the design of our current 
immunogens to expand their germline BCR-activation capabilities; 2) Engineer and characterize a modified 
variant of our immunogen that lacks specific variable domains, and 3) Design/optimize immunogens for 
macaque BCR activation. The proposed research in Project One is central to the overall activities and aims 
of our IPCAVD Program.

## Key facts

- **NIH application ID:** 9886177
- **Project number:** 5U19AI109632-08
- **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER
- **Principal Investigator:** Leonidas Stamatatos
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,997,824
- **Award type:** 5
- **Project period:** — → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9886177

## Citation

> US National Institutes of Health, RePORTER application 9886177, Immunogen Design for Specific BCR Activation (5U19AI109632-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9886177. Licensed CC0.

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