CD123-Binding Polypeptides for Redirected T-Cell Cytotoxicity
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Solution Overview
Problem
Current treatments for hematologic malignancies such as acute myeloid leukemia (AML) that target CD123 are often ineffective and associated with adverse effects, necessitating the development of molecules with increased efficiency and reduced toxicity.
Innovation Solution
Development of recombinant polypeptides with specific CD123-binding domains, engineered to minimize antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity, and capable of inducing redirected T-cell cytotoxicity by binding to both CD123-expressing cells and T-cell receptors, thereby enhancing therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current CD123-targeted treatments are used, then CD123-expressing cells can be targeted, but adverse effects and reduced efficacy occur
Solution Approach 1:
The patent modifies the antibody structure by engineering specific amino acid substitutions in the CD123-binding domain to reduce Fc-mediated effector functions while preserving antigen binding. This structural parameter change eliminates adverse effects associated with ADC and CDC while maintaining target cell binding capability
Solution Approach 2:
The invention extracts and removes the Fc region of the antibody that mediates cytotoxic effects, creating an Fc-free or Fc-modified antibody construct. This extraction eliminates the harmful ADC and CDC mechanisms while retaining the antigen-specific binding function of the variable region
2Productivity
If multi-specific protein therapeutics binding CD123 and T-cell receptor complex are used, then redirected T-cell cytotoxicity is induced, but cytokine release increases
Solution Approach 1:
The patent engineers specific amino acid substitutions in the Fc region that modulate cytokine production by T-cells while preserving the ability to induce redirected cytotoxicity. This fine-tunes the immune response parameters to reduce harmful cytokine release while maintaining therapeutic killing activity
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The engineered polypeptides demonstrate potent target-dependent T-cell cytotoxicity, reduced cytokine release, and lower adverse event risk, providing effective treatment for CD123-overexpressing disorders like AML.
Implementation Method 1
molecules that specifically bind to CD123
Implementation Method 2
inducing redirected T-cell cytotoxicity by binding to both CD123-expressing cells and T-cell receptors
Implementation Method 3
engineered to minimize antibody-dependent cell-mediated cytotoxicity
Implementation Method 4
engineered to minimize antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity
Data Source
AI summary
The present disclosure relates to protein molecules that specifically bind to CD123, which may have at least one humanized or human CD123-binding domain. Such molecules are useful for the treatment of cancer. The protein molecule binding to CD123 may have a second binding domain that binds to another target. In one embodiment, multi-specific polypeptide molecules bind both CD123-expressing cells and the T-cell receptor complex on T-cells to induce target-dependent T-cell cytotoxicity, activation, and proliferation. The disclosure also provides pharmaceutical compositions comprising the CD123-binding polypeptide molecules, nucleic acid molecules encoding these polypeptides and methods of making these molecules.