# T-cell receptor mimic affinity reagent generation using an in vivo novel immunogen strategy

> **NIH NIH R43** · ABBRATECH, INC. · 2023 · $295,460

## Abstract

ABSTRACT
Current therapeutic antibodies target the cell surface and within the external cellular environment. Yet
intracellular proteins make up half of the proteome. Having a facile means of targeting those intracellular
proteins for the generation of therapeutic antibodies would be highly desirable. Targeting MHC complexed
with neoantigens from intracellular proteins would greatly allow the generation of T cell receptor mimic
(TCRm) antibodies for development as therapeutic drugs. We have developed a unique immune-targeting
strategy that we call ‘Epivolve’ that can be used to make ‘site directed’ Abs by leveraging the modularity of
the complementarity determining region (CDR)-H2 of an Ab. Epivolve functions through the ‘evolution’ of an
Ab paratope using methods that are described in the proposal. The advantages of the in vivo method
proposed include the isolation of Abs that have a high affinity (in the low picomolar range) for the
peptide:MHC complex. This is because Abs can undergo multiple Ag challenges and affinity maturation via
somatic hyper-mutagenesis in vivo to generate antibodies with single digit pM to hundredth nM. In vivo
methods can also take advantage of transgenic animals for deriving human Abs. Affinities of TCRm Abs
produced through phage display tend to lie in the moderate nanomolar range (≈50–300 nM) and require
further in vitro protein engineering. For this proposal, Abbratech will apply its novel site-directed Epivolve
technology along with an improved rabbit single B cell sorting platform for the efficient discovery of TCRm
Abs. The Epivolve method overcomes tolerance. And one of our goals is to generate antibodies in as little
as 5 weeks. High-affinity, neoantigen:MHC-specific TCRm Abs have proven difficult to produce in large
numbers by either traditional phage or hybridoma approaches. Enhanced technologies for the generation of
TCRm Abs within a short period of time offer exciting opportunities to accelerate future TCRm Ab discovery.

## Key facts

- **NIH application ID:** 10599584
- **Project number:** 1R43GM149009-01
- **Recipient organization:** ABBRATECH, INC.
- **Principal Investigator:** Michael P Weiner
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $295,460
- **Award type:** 1
- **Project period:** 2023-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10599584

## Citation

> US National Institutes of Health, RePORTER application 10599584, T-cell receptor mimic affinity reagent generation using an in vivo novel immunogen strategy (1R43GM149009-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10599584. Licensed CC0.

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