# Refinement of DNA-Launched NanoParticles decorated with Apex and CD4bs B cell lineage targeting Envs (DLNP-ACEs)

> **NIH NIH U19** · WISTAR INSTITUTE · 2024 · $1,141,993

## Abstract

Project 2 - Project Summary
In order to protect against HIV-1 acquisition, antibody-based vaccines must be able to consistently elicit
broadly neutralizing antibodies (bnAbs). bnAb elicitation has proven difficult in humans and non-human
primates (NHPs), in part because of the complex developmental pathways bnAbs require to mature,
competition from off-target responses to the HIV-1 envelope glycoprotein (Env), and rare precursor B cell
frequency. In this project we will develop candidate immunogens to address each of these problems through
a variety of approaches. First, we will use structure-based and mammalian display techniques to further
enhance the germline targeting ability of our lead candidate, Q23.17 MD39. Using these approaches, we
will develop native-like trimers capable of targeting the V2-apex and CD4 binding site bnAb epitopes. These
trimer immunogens will additionally be engineered to limit off-target responses by minimizing competition
from highly immunodominant non-neutralizing antibody lineages. Furthermore, we will use these constructs
to develop novel “germline targeting SHIVs”, and through SHIV-infection will identify boosting immunogens
that can guide the development of breadth. Additionally, through structural analysis of the process of Env-
Ab coevolution, we aim to identify determinants of bnAb development in infected primates, that will further
inform our immunogen design process. Finally, we will complex these with genetic adjuvants developed in
project 1 and platform advances in project 3, as well as with our novel DNA-Launched NanoParticle (DLNP)
platform. We have shown DLNPs improve the immunogenicity while not requiring the complex cGMP
processes that hamper the pace of clinical development for traditional nanoparticle vaccines. We will then
down-select immunogens using a variety of innovative mouse models that harbor human B cell lineages,
recapitulate human B cell competition and have tunable bnAb precursor frequencies. These mice will
provide a benchmark for our lead candidates to be advanced into GMP production. We will test them in a
NHP model for heterologous challenge, and through these combined approaches, we aim to demonstrate,
for the first time, protection from heterologous tier-2 challenge in NHPs.

## Key facts

- **NIH application ID:** 10751008
- **Project number:** 5U19AI166916-02
- **Recipient organization:** WISTAR INSTITUTE
- **Principal Investigator:** Daniel Kulp
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,141,993
- **Award type:** 5
- **Project period:** 2022-12-08 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10751008

## Citation

> US National Institutes of Health, RePORTER application 10751008, Refinement of DNA-Launched NanoParticles decorated with Apex and CD4bs B cell lineage targeting Envs (DLNP-ACEs) (5U19AI166916-02). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10751008. Licensed CC0.

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