# Targeting EMP2 for the treatment of triple negative breast cancer with novel anti-EMP2 Granzyme B immunoconjugates

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2020 · $171,825

## Abstract

PROJECT SUMMARY/ABSTRACT
Immunoconjugates are designed to focus the delivery of highly cytotoxic agents to specific target cells using
monoclonal antibodies, potentially improving the therapeutic index of the agent. To this end, we propose to
deliver a cytotoxic protein payload with an anti-EMP2 IgG1 antibody. EMP2, or epithelial membrane protein-2,
is a biomarker that is highly expressed in the majority (63%; n=97) of invasive breast cancer tumors examined
compared to healthy mammary epithelium, and high EMP2 expression is observed in over 75% of triple negative
breast cancer cases examined where EMP2 is observed in both the primary tumor as well as in metastatic
lesions. As engineered recombinant antibodies hold great promise for cancer diagnostics and therapy, we have
carefully assembled a research team centered at UCLA and The University of Texas MD Anderson Cancer
Center to develop recombinant anti-EMP2 antibodies fused to the human serine protease granzyme B for
therapy. The group at UCLA has previously shown that a full length IgG1 against EMP2 promotes apoptosis
both in vitro and in vivo in a number of EMP2 positive tumors, but as new data suggests that the anti-EMP2 IgG1
can internalize rapidly, we hypothesize that it may serve as a novel candidate for drug conjugation. The use of
Granzyme B (GrB) as an immunoconjugate has been proposed as a “magic bullet” as, once delivered to the
cytoplasm of a cell, it activates apoptosis pathways with little to no induction of immunogenicity. The Mohamedali
lab has utilized human GrB as an effective payload for the generation of recombinant cell death-inducing fusion
proteins and has clearly demonstrated that GrB-containing fusion constructs have impressive and highly
selective cytotoxic effects when delivered to the cytoplasm by either antibody or growth factor cell targeting
carriers.
In this proposal, with the explicit goal of advancing the science of anti-EMP2 antibodies as well as GrB as a
cytotoxic payload for clinical testing, we will create and determine the efficacy of two anti-EMP2 IgG1- GrB
conjugates. Accordingly, the specific aims propose to design and test the efficacy of GrB linked to an anti-EMP2
IgG1 for cytotoxicity as well as start creating a preclinical package to understand its functional affinity and
stability. As the naked antibody cross-reacts between human and mouse, the toxicity profile of the
immunoconjugate, including pharmacokinetics and maximum tolerated dosage, will also be determined. Given
its high expression in a number of gynecological tumors including ovarian and endometrial, these studies will be
important to position EMP2 as a viable target for cancers in women. It will also, given the need for new toxins
with low immunogenicity, help position granzyme B in the forefront of antibody linked toxins.

## Key facts

- **NIH application ID:** 9930061
- **Project number:** 5R21CA234642-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Khalid A Mohamedali
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $171,825
- **Award type:** 5
- **Project period:** 2019-07-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9930061

## Citation

> US National Institutes of Health, RePORTER application 9930061, Targeting EMP2 for the treatment of triple negative breast cancer with novel anti-EMP2 Granzyme B immunoconjugates (5R21CA234642-02). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/9930061. Licensed CC0.

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