Small shedding blocking agents
Inventors
HAKIM, MOTTI • FRIDMAN-DROR, Anna • ALISHEKEVITZ, DROR • MEILIN, Edna • Mandel, Ilana • Ben-Moshe, Tehila • Shulman, Avidor • Sapir, Yair
Assignees
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Publication Number
US-12503510-B2
Publication Date
2025-12-23
Expiration Date
Abstract
Agents that are less than 100 kilodaltons, bind a membranal immune receptor on a surface of a cell and inhibit proteolytic cleavage of the immune receptor are provided. Methods of treating cancer and improving immunotherapy comprising administering the agents are also provided.
Core Innovation
The invention provides small shedding blocking agents that bind membranal CD28 (mCD28) and inhibit proteolytic cleavage/shedding to reduce soluble CD28 (sCD28). The agents target the CD28 extracellular domain, with emphasis on the CD28 stalk region near an MMP cleavage motif, and are described as not being Fc-containing full-size IgG and not being CD28 agonists or antagonists.
Proteolytic cleavage/shedding is described in terms of named proteases including MMP-2 and MMP-13, with ADAM10/ADAM17 also discussed. In this framework, the agents inhibit generation of sCD28 by blocking protease-mediated cleavage of mCD28 on a cell surface.
The invention further describes agent embodiments for binding CD28, including single domain/VHH/nanobody agents, Fab/scFv formats, and small molecules/peptides/aptamers/DARPins. Exemplary single domain antibodies are described as binding the CD28 stalk region and blocking cleavage by proteases, while not degrading mCD28 or inhibiting mCD28-mediated activation.
Claims Coverage
The provided independent claims are clm-00001 and clm-00017. Based on the document excerpt, claim coverage centers on two inventive features: specific single domain antibody CDR sequences and a method for generating an antibody that blocks proteolytic cleavage of mCD28 on a cell surface.
Single domain antibody with specified CDR sequences
A single domain antibody comprising three CDRs, wherein CDR1, CDR2, and CDR3 comprise amino acid sequences set forth in specified SEQ ID numbers, with alternative CDR sequence combinations provided.
Generate single domain antibody that inhibits mCD28 cleavage by proteases
A method of generating a single domain antibody that inhibits proteolytic cleavage of mCD28 on a surface of a cell, comprising obtaining a single domain antibody that binds a CD28 extracellular domain, testing binding to cell surface mCD28, selecting an antibody that binds, testing ability to block cleavage by a protease of mCD28 on a cell surface, and selecting an antibody that blocks cleavage, thereby generating an antibody that inhibits proteolytic cleavage.
Across the independent claims, the core coverage is the identification and use of single domain antibodies defined by specific CDR sequence options and the generation process for selecting antibodies that bind cell surface mCD28 and block protease-mediated proteolytic cleavage.
Stated Advantages
Improved cancer treatment by reducing soluble CD28 (sCD28) via inhibition of CD28 shedding.
Enhanced PD-1/PD-L1 immunotherapy efficacy.
Reduces proteolytic cleavage/shedding of membranal CD28 (mCD28) to decrease soluble CD28 (sCD28).
Documented Applications
Use in methods for treating cancer in a subject, with cancer types including melanoma, head and neck cancer, non-small cell lung cancer, ovarian cancer, kidney cancer, gastric cancer, and colorectal cancer.
Improving PD-1/PD-L1 based immunotherapy in a cancer patient in the context of listed cancer types.
Application of antibodies as agents that inhibit proteolytic cleavage of mCD28 on a surface of a cell by blocking protease-mediated shedding.
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