# Improving specificity of therapeutic antibodies for cancer.

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $388,830

## Abstract

Abstract
While mAb therapies have proven to be potent, controllable and effective treatment modalities for several
cancers and leukemias, marketed therapeutic anti-cancer mAb recognize extracellular or cell surface proteins,
which constitute only a small fraction of the cellular proteins and are not generally tumor specific. In contrast,
mutated or oncogenic tumor associated proteins are typically nuclear or cytoplasmic. These intracellular
proteins are usually un-druggable if they are not enzymes or receptors. Intracellular proteins are degraded in
the proteasome, processed and presented on the cell surface by MHC class I molecules as T cell epitopes that
are recognized by T cell receptors (TCR’s). We choose here to co-opt lessons from the immune system, which
has evolved the highly efficient and truly selective T cell with its TCR capable of recognizing HPV viral proteins
and phosphorylated intracellular proteins. TCR mimic (TCRm) mAb recognize peptide antigens of these key
intracellular proteins in the context of MHC on the cell surface, marry the best features of both the T cell and a
mAb and greatly extend the potential repertoire of tumor targets addressable by potent mAb. The Specific
Aims are: 1.) To identify and understand optimal cancer-specific targets for TCRm and create TCRm
to them. A. Cancer-specific HPV viral oncogenic proteins. B. Upregulated phosphopeptides in cancer
cells. We ask: What are the best epitope targets to approach with TCRm from a biological, biochemical,
biophysical, or immunological point of view? (EG, certain positions in the sequence or certain amino acids?)
Are certain classes of oncogenic proteins or biochemical structures of peptides acceptable? How do we design
better screens to discover more selective TCRm? 2.) To understand the regulation of presentation of
cancer-specific epitopes in HLA on the cell surface and to characterize the changes in the unique HLA
ligandome and its potential effect on immunotherapy. For example, can we modulate the expression of the
epitopes or the antigen presentation machinery to our advantage? This may be of particular relevance to the
phosphorylated peptides introduced in Aim 1B.? And equally important, how is the MHC ligandome generally
affected by these drugs? The manipulation of the ligandome may afford a vast array of new targets for TCRm,
T cell therapy and immune checkpoint blockade. 3.) To develop proteomic and genetic tools to help guide
us to picking epitopes and predicting which may be safe? Cross-reactivities of the TCR based agents to
off-target tissues have resulted in serious, sometimes fatal, adverse events. As one solution, we are
developing the PresentER minigene-based system, which relies on a pool of genetically encoded MHC-I
ligands individually expressed and presented in mammalian cells. We will apply PresentER to the TCRm we
develop. 4.) To contrast and compare therapeutic TCRm platforms for optimal efficacy. We will conduct
animal model therapy trials i...

## Key facts

- **NIH application ID:** 9880468
- **Project number:** 2R01CA055349-26
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** DAVID A SCHEINBERG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $388,830
- **Award type:** 2
- **Project period:** 1991-09-26 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9880468

## Citation

> US National Institutes of Health, RePORTER application 9880468, Improving specificity of therapeutic antibodies for cancer. (2R01CA055349-26). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9880468. Licensed CC0.

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