Decoupling the Functional Pleiotropy of Stem Cell Factor by Tuning c-Kit Signaling

Area of Science:

• Biochemistry
• Molecular Biology
• Immunology

Background:

• Growth factors and cytokines often exhibit pleiotropy due to widespread receptor expression, limiting their therapeutic potential.
• Stem cell factor (SCF) stimulates hematopoietic progenitor expansion via c-Kit but can cause toxicity by activating mast cells.
• Pleiotropy poses a significant challenge in developing effective and safe cytokine-based therapeutics.

Purpose of the Study:

• To engineer a mechanism-based partial agonist of SCF that selectively targets hematopoietic progenitors.
• To reduce the anaphylactic side effects associated with SCF administration.
• To demonstrate the therapeutic efficacy of a biased SCF agonist in preclinical models.

Main Methods:

• Engineered an SCF variant to impair c-Kit receptor dimerization, thereby modulating downstream signaling.
• Assessed the biased activation of hematopoietic progenitors versus mast cells in vitro and in vivo.
• Evaluated the efficacy and safety of the SCF partial agonist in mouse models of anaphylaxis, radioprotection, and hematopoietic expansion.

Main Results:

• The engineered SCF partial agonist demonstrated biased activation of hematopoietic progenitors over mast cells.
• In vivo studies showed retained therapeutic efficacy for hematopoietic expansion and radioprotection.
• The SCF partial agonist exhibited significantly reduced anaphylactic off-target effects compared to wild-type SCF.

Conclusions:

• Mechanism-based engineering of partial agonists can overcome pleiotropy limitations of growth factors and cytokines.
• Tuning receptor dimerization and signaling thresholds offers a strategy for developing safer and more effective therapeutics.
• This approach has broad applicability to other dimeric receptor-ligand systems in drug development.