# Developing novel bispecific antibodies for cancer treatment

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2022 · $487,412

## Abstract

PROJECT SUMMARY
The overall goal of this project is to improve activities of therapeutic antibodies against cancer
metastasis through developing novel bispecific antibodies (BsAbs). The central hypothesis of this project is that
BsAbs designed with one specificity for a receptor or marker overexpressed on the cancer cell surface and the
other specificity for a soluble growth factor or cytokine abundant in the tumor microenvironment induce co-
phagocytosis of the growth factor or cytokine in the tumor microenvironment along with the co-targeted cancer
cells via antibody-mediated cellular phagocytosis (ADCP) and thereby produce stronger antitumor activities
than simple combination of 2 parental antibodies. The applicant has developed a pair of BsAbs, one mouse
and one human, using a new BsAb format targeting human epidermal growth factor receptor-2 (HER2), an
oncogenic driver that is emerging as a promising target for genomically informed therapy across a variety of
cancer types beyond breast and gastric cancer, and targeting vascular endothelial growth factor A (VEGFA),
another key driver that promotes tumor angiogenesis and suppresses tumor immune responses in the tumor
microenvironment. Preliminary studies with the BsAbs showed remarkable anti-metastasis activity and
prolonged survival in mouse tumor models. In the work proposed, three specific aims will be rigorously
pursued: Aim 1 is to test the working hypothesis that the BsAbs exert stronger antitumor activities than simple
combination of the 2 parental antibodies through inducing VEGFA co-phagocytosis via ADCP. Aim 2 is to
determine the extent to which adaptive immune response is involved in the mechanisms of action of the BsAbs
against metastasis of syngeneic mouse tumor models. Aim 3 is to assess the translational potential of the
BsAbs against colorectal cancer patient-derived xenografts (PDXs) in humanized mice. The proposed work will
be carried out through 1) investigating the role of engagement of FcγR in BsAb-mediated VEGFA co-
phagocytosis and in BsAb-mediated antitumor activity, 2) analyzing the immune landscape in the tumor
microenvironment and detecting presence of antigen-specific T cells upon treatment with BsAb vs with simple
combination of 2 parental antibodies with and without FcγR blockade, and 3) determining the therapeutic
activity of the BsAbs against HER2-overexpressing colorectal cancer PDXs in humanized mice. The work is
expected to demonstrate that VEGFA co-phagocytosis by the BsAbs is a key mechanism by which the BsAbs
exert stronger antitumor activity than simple combination of the 2 parental antibodies in the mouse models, and
that T cell-mediated activities play an additional important role in synergizing the BsAb's antitumor activity. The
impact of this work is expected to be high because if the study is successful, the findings will support future
clinical testing of BsAbs to treat metastasis and recurrence of HER2-overexpressing colorectal cancer and
developme...

## Key facts

- **NIH application ID:** 10441600
- **Project number:** 5R01CA262288-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Zhen Fan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $487,412
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10441600

## Citation

> US National Institutes of Health, RePORTER application 10441600, Developing novel bispecific antibodies for cancer treatment (5R01CA262288-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10441600. Licensed CC0.

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