Novel anti-denatured collagen humanized antibody D93 inhibits angiogenesis and tumor growth: An extracellular matrix-based therapeutic approach

Pernasetti, Flavia; Nickel, Jeffrey C.; Clark, Derek; Baeuerle, Patrick A.; Epps, Dennis Van; Freimark, Bruce

doi:10.3892/ijo.29.6.1371

Cited by 14 publications

(26 citation statements)

References 23 publications

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“…Moreover, endothelial cell interactions with denatured collagen resulted in an ϳ50% reduction of IGFBP-4 mRNA as compared with triple-helical collagen. These findings suggest that endothelial cell interactions with denatured collagen-IV, which is known to be present within the vascular basement membrane of angiogenic blood vessels in vivo (10,11,(13)(14)(15)(16)(17)34), may suppress the expression of IGFBP-4.…”

Section: Endothelial Cell Interactions With Denatured Collagen Type Imentioning

confidence: 84%

“…The stimulatory and inhibitory factors within a particular microenvironment are likely derived from multiple sources and may impact multiple cell types that contribute to blood vessel formation. In addition to the numerous cell types that govern angiogenesis, a complex network of ECM proteins that surround pre-existing blood vessels has been shown to regulate neovascularization (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). The majority of quiescent vessels are surrounded by intact basement membranes.…”

Section: Discussionmentioning

confidence: 99%

“…However, the cellular and molecular mechanisms by which biomechanical changes in ECM structure control new vessel development are poorly understood. Previous studies have shown that denatured collagen type IV is often associated with angiogenic vessels in vivo, and cellular interactions with denatured collagen have been shown to regulate angiogenesis in multiple models (10,11,(13)(14)(15)(16)(17)34). Our previous observations suggested that disruption of tumor cell interactions with denatured collagen might enhance the expression of IGFBP-4, a member of the insulin-like growth factor-binding protein family.…”

Section: Endothelial Cell Interactions With Denatured Collagen Type Imentioning

confidence: 99%

See 2 more Smart Citations

Insulin-like Growth Factor Binding Protein-4 Differentially Inhibits Growth Factor-induced Angiogenesis

Contois

Nugent

Caron

et al. 2012

Journal of Biological Chemistry

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Background:We examined the impact of insulin-like growth factor binding protein-4 (IGFBP-4) on growth factor-induced angiogenesis in vivo. Results: IGFBP-4 inhibited IGF-1 and FGF-2, but not VEGF-induced angiogenesis, and this inhibition depended on p38 MAPK activity. Conclusion:The anti-angiogenic activity of IGFBP-4 depends in part on p38 MAPK. Significance: New insight is provided into how blood vessels respond to endogenous inhibitors during growth factor-stimulated angiogenesis.

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Section: Endothelial Cell Interactions With Denatured Collagen Type Imentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Endothelial Cell Interactions With Denatured Collagen Type Imentioning

confidence: 99%

See 1 more Smart Citation

Insulin-like Growth Factor Binding Protein-4 Differentially Inhibits Growth Factor-induced Angiogenesis

Contois

Nugent

Caron

et al. 2012

Journal of Biological Chemistry

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“…Given previous studies indicating that blocking the HU177 epitope selectively inhibited endothelial cell adhesion to denatured collagen type IV but not native intact collagen type IV 15 and inhibited angiogenesis in vivo, 15,18 the reduction in cellular proliferation within these tumors could be due to multiple mechanisms, including inhibition of angiogenesis given the known role of angiogenesis in regulating tumor growth.…”

Section: The Hu177 Epitope Regulates Angiogenesis and Stromal Cell Acmentioning

confidence: 99%

Inhibition of Ovarian Tumor Growth by Targeting the HU177 Cryptic Collagen Epitope

Caron

Ames

Contois

et al. 2016

The American Journal of Pathology

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Evidence suggests that stromal cells play critical roles in tumor growth. Uncovering new mechanisms that control stromal cell behavior and their accumulation within tumors may lead to development of more effective treatments. We provide evidence that the HU177 cryptic collagen epitope is selectively generated within human ovarian carcinomas and this collagen epitope plays a role in SKOV-3 ovarian tumor growth in vivo. The ability of the HU177 epitope to regulate SKOV-3 tumor growth depends in part on its ability to modulate stromal cell behavior because targeting this epitope inhibited angiogenesis and, surprisingly, the accumulation of a-smooth muscle actineexpressing stromal cells. Integrin a10b1 can serve as a receptor for the HU177 epitope in a-smooth muscle actineexpressing stromal cells and subsequently regulates Erkdependent migration. These findings are consistent with a mechanism by which the generation of the HU177 collagen epitope provides a previously unrecognized a 10 b 1 ligand that selectively governs angiogenesis and the accumulation of stromal cells, which in turn secrete protumorigenic factors that contribute to ovarian tumor growth. Our findings provide a new mechanistic understanding into the roles by which the HU177 epitope regulates ovarian tumor growth and provide new insight into the clinical results from a phase 1 human clinical study of the monoclonal antibody D93/TRC093 in patients with advanced malignant tumors. (Am J Pathol 2016 http://dx

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“…During collagen remodeling, large portions of collagens are degraded and denatured by proteolytic enzymes, which can be explored for diagnostic and therapeutic purposes. Since unstructured proteins are not ideal targets for rational drug design, library approaches have been employed to develop monoclonal antibody (1,2) and peptide probes (3) that specifically bind to cryptic sites in collagen strands that become exposed when denatured. However, these probes suffer from poor pharmacokinetics (4), and/or low specificity, and binding affinity (5).…”

mentioning

confidence: 99%

Targeting collagen strands by photo-triggered triple-helix hybridization

Foss

Summerfield

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

175

244

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Collagen remodeling is an integral part of tissue development, maintenance, and regeneration, but excessive remodeling is associated with various pathologic conditions. The ability to target collagens undergoing remodeling could lead to new diagnostics and therapeutics as well as applications in regenerative medicine; however, such collagens are often degraded and denatured, making them difficult to target with conventional approaches. Here, we present caged collagen mimetic peptides (CMPs) that can be phototriggered to fold into triple helix and bind to collagens denatured by heat or by matrix metalloproteinase (MMP) digestion. Peptidebinding assays indicate that the binding is primarily driven by stereo-selective triple-helical hybridization between monomeric CMPs of high triple-helical propensity and denatured collagen strands. Photo-triggered hybridization allows specific staining of collagen chains in protein gels as well as photo-patterning of collagen and gelatin substrates. In vivo experiments demonstrate that systemically delivered CMPs can bind to collagens in bones, as well as prominently in articular cartilages and tumors characterized by high MMP activity. We further show that CMP-based probes can detect abnormal bone growth activity in a mouse model of Marfan syndrome. This is an entirely new way to target the microenvironment of abnormal tissues and could lead to new opportunities for management of numerous pathologic conditions associated with collagen remodeling and high MMP activity.A s the most abundant protein in mammals, collagens play a crucial role in tissue development and regeneration, and their structural or metabolic abnormalities are associated with debilitating genetic diseases and various pathologic conditions. Although collagen remodeling occurs during development and normal tissue maintenance, particularly for renewing tissues (e.g., bones), excess remodeling activity is commonly seen in tumors, arthritis, and many other chronic wounds. During collagen remodeling, large portions of collagens are degraded and denatured by proteolytic enzymes, which can be explored for diagnostic and therapeutic purposes. Since unstructured proteins are not ideal targets for rational drug design, library approaches have been employed to develop monoclonal antibody (1, 2) and peptide probes (3) that specifically bind to cryptic sites in collagen strands that become exposed when denatured. However, these probes suffer from poor pharmacokinetics (4), and/or low specificity, and binding affinity (5).We envisioned that triple helix, the hallmark structural feature of collagen, could provide a unique targeting mechanism for the denatured collagens. The triple helix is nearly exclusively seen in collagens except as small subdomains in a few noncollagen proteins (6). Considering its striking structural similarity to the DNA double helix in terms of multiplex formation by periodic interchain hydrogen bonds along the polymer backbone (6), we thought that a small peptide sequence with strong triple-helix prope...

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Novel anti-denatured collagen humanized antibody D93 inhibits angiogenesis and tumor growth: An extracellular matrix-based therapeutic approach

Cited by 14 publications

References 23 publications

Insulin-like Growth Factor Binding Protein-4 Differentially Inhibits Growth Factor-induced Angiogenesis

Insulin-like Growth Factor Binding Protein-4 Differentially Inhibits Growth Factor-induced Angiogenesis

Inhibition of Ovarian Tumor Growth by Targeting the HU177 Cryptic Collagen Epitope

Targeting collagen strands by photo-triggered triple-helix hybridization

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