Blocking antibodies against integrin-α3, integrin-αM, and integrin-αMβ2 de-differentiate myofibroblasts and reverse lung and kidney fibroses in a mouse model

Fibrosis is involved in 45% of deaths in the United States, and no treatment exists to reverse the progression of the disease. Myofibroblasts are key to the progression and maintenance of fibrosis. We investigated features of cell adhesion necessary for monocytes to differentiate into myofibroblasts, seeking to identify pathways key to myofibroblast differentiation. Blocking antibodies against integrins α3, αM, and αMβ2 de-differentiate myofibroblasts in vitro , lower the pro-fibrotic secretome of myofibroblasts, and reverse fibrosis in vivo . Decorin’s collagen-binding peptide can target these blocking antibodies to both fibrotic lungs and fibrotic kidneys, reducing the dose of antibody necessary to reverse fibrosis. This targeted immunotherapy blocking key integrins may be an effective therapeutic for the treatment and reversal of fibrosis. ### Competing Interest Statement MJVW and JH are authors on a patent regarding this submission * (α-SMA) : alpha-smooth muscle actin (CBP-α-αMβ2) : CBP-functionalized blocking antibodies against αMβ2 (CBP-α-αM) : CBP-functionalized blocking antibodies against αM (CBP-α-α3) : CBP-functionalized blocking antibodies against α3 (CBP) (LRELHLNNNC) : collagen-binding peptide (FAs) : focal adhesions (FCS) : fetal calf serum (FBs) : Fibrillar adhesions (CY7-α-α3) : Fluorescently labeled Cy7-blocking antibodies against α3 (CY7-α-αMβ2) : Fluorescently labeled Cy7-blocking antibodies against αMβ2 (CY7-α-αM) : Fluorescently labeled Cy7-blocking antibodies against αM (antibody which stabilizes the association of integrin α2β1) : Gi14 (MRC-5) : Human fibroblasts (called MAC1) : heterodimer αMβ2 (IL12p40) : IL-12 subunit p40 (α3) : Integrin-α3 (αM) : Integrin-αM (β2) (CD18) : Integrin-β2 (MCP1) : macrophage-chemotactic protein-1 (NIH-3T3) : mouse fibroblasts (α-αMβ2) : blocking antibodies against αMβ2 (α-αM) : blocking antibodies against αM (α-α3) : blocking antibodies against α3 (PBMC) : peripheral blood mononuclear cells (PBS) : phosphate buffered saline (SFM) : serum-free media (TGFβ) : Transforming growth factor β (TNFα) : Tumor necrosis factor α (UUO) : Unilateral ureteral obstruction