# Effector mechanisms and therapeutic potential of MUC1 vaccine-elicited human antibodies

> **NIH NIH F32** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $45,366

## Abstract

Project Summary
Cancer cells undergo changes that the immune system can recognize, and this can be leveraged for therapy.
Direct-targeting antibodies that recognize such changes can operate via multiple mechanisms, including
blocking oncogenic signaling, serving as Trojan horses carrying toxic compounds, coordinating innate immune
engagement for cytotoxicity through cellular and non-cellular means, and promoting antigen uptake to
jumpstart adaptive immunity that can provide durable protection. We recently generated a dozen high-affinity
fully human monoclonal antibodies (mAbs) that recognize a tumor-specific hypoglycosylated form of Mucin-1
(MUC1), a form that is present and overexpressed in >80% of all cancers. Our anti-MUC1 mAbs are different
and unique from other humanized murine anti-MUC1 mAbs, having been isolated from a healthy human
individual receiving the MUC1-100mer peptide vaccine. They have undergone selection and affinity maturation
in a healthy immune environment. Importantly, in all vaccinated individuals that generated an antibody
response to MUC1, there have been no adverse events in 8 years, increasing the likelihood that these agents
will be safe. Our new preliminary data show these mAbs can mediate immune effector functions in vitro. Our
objective is to provide preclinical data on the safety, efficacy and the mechanism of action of our fully-human
MUC1 antibodies. We hypothesize they can safely cause tumor regression in vivo and will reveal fundamental
aspects of antibody-antigen interactions that will inform future therapeutic antibody design. In the first aim, we
plan to test the safety, efficacy and mechanism(s) of action of our anti-MUC1 antibodies against huMUC1-
transgenic murine tumors in immunocompetent mice expressing both the human MUC1 gene and human
antibody receptor genes, and against MUC1+ human tumor xenografts in immunodeficient huMUC1-Tg mice.
We will monitor weight, food intake, temperature, and compare histological tumor sections to those of other
tissues to assess safety and cross-reactivity with normal tissues. We will compare our MUC1 antibodies
against well-characterized FDA-approved mAbs such as rituximab (anti-CD20) and trastuzumab (anti-Her2) for
their ability to control tumors co-expressing huMUC1 together with huCD20 or huHer2. We will assess whether
the MUC1 antibodies mediate effector functions through innate or adaptive immune mechanisms. In the
second aim, we will determine the requirements of MUC1/ anti-MUC1 interactions that mediate immune
effector functions. Using our panel of 12 anti-huMUC1 mAbs and four MUC1 constructs, we will evaluate first in
vitro the requirements of antibody affinity, level of antigen expression, epitope proximity to the cell membrane,
and membrane location on antibody-dependent cellular cytotoxicity (ADCC), phagocytosis (ADCP),
complement-dependent cytotoxicity (CDC), and antibody internalization. Key findings from in vitro studies will
be validated in vivo. Together ...

## Key facts

- **NIH application ID:** 9851739
- **Project number:** 5F32CA236457-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Michelle L Miller
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,366
- **Award type:** 5
- **Project period:** 2019-01-01 → 2020-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851739

## Citation

> US National Institutes of Health, RePORTER application 9851739, Effector mechanisms and therapeutic potential of MUC1 vaccine-elicited human antibodies (5F32CA236457-02). Retrieved via AI Analytics 2026-06-13 from https://api.ai-analytics.org/grant/nih/9851739. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*