Targeting inflammatory sites through collagen affinity enhances the therapeutic efficacy of anti-inflammatory antibodies

Abstract

Enhancing the therapeutic efficacy of drugs for inflammatory diseases is of high demand. One possible approach is targeting drugs to the extracellular matrix of the inflamed area. Here, we target collagens in the matrix, which are inaccessible in most tissues yet are exposed to the bloodstream in the inflamed area because of vascular hyperpermeability. We conferred collagen affinity to anti–tumor necrosis factor-α (α-TNF) antibody by conjugating a collagen-binding peptide (CBP) derived from the sequence of decorin. CBP–α-TNF accumulated in the inflamed paw of the arthritis model, and arthritis development was significantly suppressed by treatment with CBP–α-TNF compared with the unmodified antibody. Similarly, CBP–anti-transforming growth factor-β (α–TGF-β) accumulated in the inflamed lung of pulmonary fibrosis model and significantly suppressed pulmonary fibrosis compared with the unmodified antibody. Together, collagen affinity enables the anticytokine antibodies to target arthritis and pulmonary fibrosis accompanied by inflammation, demonstrating a clinically translational approach to treat inflammatory diseases.

Systemically Administered, Target-Specific, Multi-Functional Therapeutic Recombinant Proteins in Regenerative Medicine

“…Some of these regenerative medicine-intended homing peptides are more general, i.e. can be applied to all injuries, such as identifying peptides capable of binding to the angiogenic or reactive (or towards diseases with inflammatory component) blood vessels forming at the injured tissues [26], or peptides binding to the extracellular matrix (ECM) collagen exposed in inflammatory conditions [32]. Regenerative medicine intended vascular homing peptides have been described towards specific clinical situations, such as targeting blood clots that form after an acute, traumatic tissue injury [33] or towards angiogenetic blood vessels at early [34] and late stage of wound healing when granulation tissue matures to scar tissue [26].…”

“…This can be considered as a remarkable feat in the light of studies demonstrating that the DCN core protein homes to angiogenesis [65,66] and has been used as a delivery vehicle for other therapeutics [67]. Most recently, a collagen binding peptide derived from the DCN sequence was used as a delivery vehicle for anti-inflammatory and -fibrotic therapeutics to inflammatory diseases [32]. Furthermore, on top of these homing features DCN possesses, the naturally occurring glycosaminoglycan (GAG) in DCN can bind to α2β1-integrins on angiogenic endothelial cells [68].…”

Systemically Administered, Target-specific, Multi-functional Therapeutic Recombinant Proteins in Regenerative Medicine

“…Some of them are more general, i.e. can be applied to all injuries, such as identifying peptides capable of binding to the angiogenic or inflammatory blood vessels forming at the injured tissues [24] , or peptides binding to the extracellular matrix (ECM) collagen exposed in inflammatory conditions [30] . Additional targeting peptides have been described towards more specific clinical molecular targets such as blood clots after an injury [31] , angiogenetic blood vessels at early [32] and late stage of wound healing when granulation tissue matures to scar tissue [24] , ruptured blood vessels [33] , transected nerves [34] , intestine with burn injury [35,36] , brain injury after a traumatic breakage of the blood-brain barrier [37,38] , bone tissue [39][40][41] , bacterial infections [42] or simply illuminating neural structures during surgery [43,44] (Table 1).…”

“…This can be considered as a remarkable feat in the light of studies demonstrating that the DCN core protein homes to angiogenesis [63,64] and has been used as a delivery vehicle for other therapeutics [65] . Most recently a collagen binding peptide derived from the DCN sequence was used as a delivery vehicle for antiinflammatory and -fibrotic therapeutics to inflammatory diseases [30] . Furthermore, naturally occurring glycosaminoglycan (GAG) in DCN can bind to α2β1-integrins on angiogenic endothelial cells [66] .…”

“…Some of these could also be applied to regenerative medicine with a very specific indication. Large number of such molecules carry either anti-or pro-inflammatory protein in hopes of deciphering immune response [30,[76][77][78][79][80][81][82] . Recently, a homing peptide targeting tumor ECM delivered tumor necrosis factor-α (TNFα) to ECM rich regions in tumors and caused immune cell infiltration and subsequent immune cell-induced ECM breakage [77] .…”