Shedding blocking agents with increased stability
Inventors
HAKIM, MOTTI • FRIDMAN-DROR, Anna • Mandel, Ilana • Ben-Moshe, Tehila • Sapir, Yair • Shulman, Avidor • ZELTSBURG, Lilach Chen • Lewkowicz, Ayala
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12589163-B2
Publication Date
2026-03-31
Expiration Date
Abstract
Agents comprising at least two moieties separated by a linker, wherein a first moiety binds mCD28 on a surface of a cell and inhibits proteolytic cleavage of the mCD28 and wherein a second moiety increases stability of the first moiety are provided. Methods of treating cancer and improving immunotherapy comprising administering the agents are also provided.
Core Innovation
The invention provides an agent comprising at least two moieties separated by a linker. A first moiety binds membranal CD28 (mCD28) on the surface of a cell and inhibits proteolytic cleavage of said mCD28, and a second moiety increases stability of the first moiety. The linker is selected from rigid peptide linkers, peptide linkers comprising a helix motif, linkers comprising at least 15 amino acids, rigid linkers comprising at least 30 amino acids, linkers comprising at least one cysteine residue, and linkers comprising at least one C-terminal cysteine residue.
The agent is not a CD28 agonist and not a CD28 antagonist. Increased stability of the first moiety is described in terms of increased stability in blood and/or reduced clearance from blood, reduced renal filtration, and reduced lysosomal degradation. Embodiments also include stabilization provided by polyethylene glycol (PEG) forms and/or human serum albumin (HSA) binding polypeptides or HSA binding single domain antibodies.
The patent further describes methods for generating and selecting such agents. A first moiety that binds mCD28 on a cell surface and inhibits proteolytic cleavage is obtained, linked to a second moiety by a linker to produce a linked agent, and tested for binding to mCD28 and inhibition of proteolytic cleavage, with linked agents that bind mCD28 and inhibit proteolytic cleavage selected. Embodiments include a host cell comprising vectors encoding the selected agent.
Claims Coverage
The document contains two independent claims: one directed to the agent and one directed to a method of generating the agent. Across the independent claims, the core inventive features include mCD28 binding and inhibition of proteolytic cleavage combined with a second moiety that increases stability, specified linker formats, and a generate-test-select process with host-cell embodiments.
Agent with mCD28 binding, cleavage inhibition, and stabilizing moiety
An agent comprising at least two moieties separated by a linker, wherein a first moiety binds membranal CD28 (mCD28) on a surface of a cell and inhibits proteolytic cleavage of said mCD28 and wherein a second moiety increases stability of said first moiety.
Linker formats including rigid, helix-motif, and cysteine-containing linkers
The linker is at least one of: a rigid peptide linker; a peptide linker comprising a helix motif; comprising at least 15 amino acids; a rigid linker comprising at least 30 amino acids; comprising at least one cysteine residue; and comprising at least one C-terminal cysteine residue.
Generating and selecting linked agents targeting mCD28 cleavage inhibition
A method of generating an agent comprising obtaining a first moiety that binds mCD28 on a cell surface and inhibits proteolytic cleavage of said mCD28, linking said first moiety to a second moiety by a linker to produce a linked agent, testing binding of said linked agent to mCD28 on a surface of a cell and inhibition of proteolytic cleavage of said mCD28, and selecting a linked agent that binds mCD28 on a cell surface and inhibits proteolytic cleavage of said mCD28, including host-cell embodiments encoding the selected agent.
Across the independent claims, the coverage combines mCD28 binding, inhibition of proteolytic cleavage, and increased stability provided by a second moiety, together with specified linker formats and a method that generates, tests, and selects such linked agents, including host-cell embodiments.
Stated Advantages
Inhibits proteolytic cleavage of membranal CD28 (mCD28), thereby decreasing soluble CD28 (sCD28) levels.
Increases stability of the first moiety, including increased stability in blood and/or reduced clearance from blood.
Reduces renal filtration.
Reduces lysosomal degradation.
Not explicitly described as a CD28 agonist or CD28 antagonist.
Documented Applications
Cancer treatment and/or prevention by decreasing soluble CD28 (sCD28) levels, including improving PD-1/PD-L1 based immunotherapy in a subject.
Interested in licensing this patent?