Methods of treating cancer using multi-specific binding proteins that bind NKG2D, CD16 and a tumor-associated antigen
Inventors
Cuillerot, Jean-Marie • DeRose, Mark • Morgan, Christopher Ryan • Naill, Michael C. • Shah, Avni
Assignees
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Publication Number
US-12377144-B2
Publication Date
2025-08-05
Expiration Date
Abstract
This disclosure relates to methods of treating cancer using multi-specific binding proteins that bind NKG2D, CD16 and a tumor-associated antigen such as HER2. Provided are uses of the multi-specific binding protein in combination with a corticosteroid to reduce the risk of infusion-related reactions. Also provided are uses of the multi-specific binding protein in treating cancer that has low or moderate HER2 expression level. The present disclosure also relates to pharmaceutical formulations comprising the multi-specific binding proteins.
Core Innovation
The invention relates to a method of treating hormone-receptor-positive breast cancer displaying HER2 expression scored as 1+ or 2+ by immunohistochemistry, without ERBB2 gene amplification for the 2+ score. The method administers a therapeutically effective amount of a multi-specific binding protein that comprises a first antigen-binding site binding NKG2D, a second antigen-binding site binding HER2, and an antibody Fc domain or third antigen-binding site binding CD16. Disclosed binding protein formats encompass Fab, scFv, and A49-F3′-TriNKET-Trastuzumab.
The multi-specific construct A49-F3′-TriNKET-Trastuzumab enhances NK-cell-mediated lysis of hormone-receptor-positive ZR75-1 and MCF-7 breast cancer cells, BT-20 cells, and Hs578T cells, while exhibiting limited killing of healthy cardiomyocytes. The disclosure also provides high-concentration formulations, infusion-reaction mitigation, and evaluation of protein charge and purity across diverse pH values and excipients. Therapeutic regimens are described as monotherapy or in combination with other therapeutic agents.
Claims Coverage
The provided claims identify one independent claim comprising two inventive features covering a method of treating specified hormone-receptor-positive breast cancer using a multi-specific binding protein.
Treatment of specified hormone-receptor-positive breast cancer
The method treats breast cancer that is positive for a hormone receptor and displays HER2 expression scored as 1+ by immunohistochemistry, or scored as 2+ by immunohistochemistry without ERBB2 gene amplification by in situ hybridization.
Multi-specific binding protein with NKG2D, HER2, and CD16 binding
The multi-specific binding protein comprises a first antigen-binding site that binds NKG2D, a second antigen-binding site that binds HER2, and an antibody Fc domain or portion thereof sufficient to bind CD16, or a third antigen-binding site that binds CD16.
The independent claim combines administration of a multi-specific binding protein targeting NKG2D, HER2, and CD16 with the treatment of hormone-receptor-positive breast cancer displaying specified HER2 expression status.
Stated Advantages
A49-F3′-TriNKET-Trastuzumab enhances NK-cell-mediated lysis of hormone-receptor-positive, HER2-medium ZR75-1 and HER2-low MCF-7 breast cancer cells, with limited killing of healthy cardiomyocytes.
In reported low-HER2 models, the construct produces greater maximum lysis of BT-20 cells than trastuzumab and promotes KHYG-1-CD16V-mediated killing of Hs578T cells.
Formulation studies report high-concentration material stability under tested storage conditions, though conflicting excerpts state that stability criteria and study designs are provided without stability results.
Documented Applications
Treatment of hormone-receptor-positive breast cancer with HER2 expression scored as IHC 1+, or scored as IHC 2+ without ERBB2 gene amplification by in situ hybridization, using a multi-specific binding protein targeting NKG2D, HER2, and CD16.
Clinical administration as monotherapy or in combination with pembrolizumab, nivolumab, or nab-paclitaxel.
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