PF-03475952: a potent and neutralizing fully human anti-CD44 antibody for therapeutic applications in inflammatory diseases

Runnels, Herbert A.; Weber, Gregory L.; Jiang, Min; Kudlacz, Elizabeth M.; Zobel, James; Donovan, Carol; Thiede, Mark A.; Zhang, Jun; Alpert, R.; Salafia, Michelle A.; Milici, Anthony J.; Burdette, Douglas; Bell, Robert J.; Beebe, Jean S.; Xu, Xu

doi:10.1007/s12325-010-0010-0

Cited by 21 publications

(10 citation statements)

References 16 publications

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“…A fully human IgG2 anti-CD44 neutralizing antibody (PF-03475952 developed by Pfizer) was reported for therapeutic applications in inflammatory diseases such as rheumatoid arthritis [317]. A humanized anti-CD44 neutralizing antibody (RG7356 developed by Roche) directly induced chronic lymphocytic leukemia cells to undergo caspase-dependent apoptosis [253].…”

Section: Ha As Therapeuticmentioning

confidence: 99%

Hyaluronan as a therapeutic target in human diseases

Liang

Jiang

Noble

2016

Advanced Drug Delivery Reviews

178

117

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Accumulation and turnover of extracellular matrix is a hallmark of tissue injury, repair and remodeling in human diseases. Hyaluronan is a major component of the extracellular matrix and plays an important role in regulating tissue injury and repair, and controlling disease outcomes. The function of hyaluronan depends on its size, location, and interactions with binding partners. While fragmented hyaluronan stimulates the expression of an array of genes by a variety of cell types regulating inflammatory responses and tissue repair, cell surface hyaluronan provides protection against tissue damage from the environment and promotes regeneration and repair. The interactions of hyaluronan and its binding proteins participate in the pathogenesis of many human diseases. Thus, targeting hyaluronan and its interactions with cells and proteins may provide new approaches to developing therapeutics for inflammatory and fibrosing diseases. This review focuses on the role of hyaluronan in biological and pathological processes, and as a potential therapeutic target in human diseases.

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Section: Ha As Therapeuticmentioning

confidence: 99%

Hyaluronan as a therapeutic target in human diseases

Liang

Jiang

Noble

2016

Advanced Drug Delivery Reviews

178

117

View full text Add to dashboard Cite

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“…By binding to CD44 it leads to inhibition of HA binding and thereby causes a loss of CD44 on the cell surface. The putative effect on drug resistance would have to be elucidated further in tumor settings [150].…”

Section: Experimental Antagonization and Drug Resistancementioning

confidence: 99%

CD44 in hematological neoplasias

2011

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“…The current study strongly enhances insight into the functional significance of CD44 v isoforms in EAE and MS pathogenesis. Although we are well aware of the limitations of animal models of inflammatory diseases including EAE (58), our results collectively show that modulation of CD44 v isoform expression and function can be considered for directed therapeutic approaches for MS. CD4 hi CD44 v10+ T cells could be blocked systemically by anti‐CD44 v10 antibodies before entering the brain; similar strategies are already actively being pursued for patients with rheumatoid arthritis, by targeting synovial fluid cells with a specific anti‐CD44 mAb (59), and in cancer therapy (60, 61).…”

Section: Discussionmentioning

confidence: 99%

CD44 variant isoforms control experimental autoimmune encephalomyelitis by affecting the lifespan of the pathogenic T cells

et al. 2013

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CD44 variant (CD44(v)) isoforms play important roles in the development of autoimmune disorders, including colitis and arthritis, but their role in multiple sclerosis (MS) has been explored only to a limited extent. We determined the functional relevance of CD44(v) isoforms in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). Genetic ablation of CD44(v7) and CD44(v10) isoforms significantly reduced the clinical EAE burden, as well as the number of inflammatory infiltrates. CD44(v7) and CD44(v10) expression on both memory T and antigen-presenting cells, participated in the development of adoptive transfer EAE. Significantly reduced mRNA expression of Th1 signature genes was detected in the brains of CD44(v10-/-) mice compared with those of CD44(WT) mice. Furthermore, forkhead transcription factor 3 (Foxp3), Bcl-2, and inducible nitric oxide synthase (iNOS) levels were reduced in CD44(v10-/-) brains, whereas active caspase-3 was elevated. Brain-infiltrating CD4(hi)CD44(v10+) T cells preceded EAE onset and paralleled disease severity in wild-type but not in CD44(v7-/-) and CD44(v10-/-) mice. CD44(v7) and CD44(v10) expression contributed to EAE by increasing the longevity of autoreactive CD4(hi)panCD44(hi) T cells. Accordingly, the absence of CD44(v7) and CD44(v10) led to increased apoptosis in the inflammatory infiltrates and reduced Th1 responses, resulting in marked disease reduction. Although absent in noninflamed human brains, we detected CD44(v3), CD44(v7), and CD44(v10) isoforms on glial cells and on perivascular infiltrating cells of MS lesions. We conclude that CD44(v7) and CD44(v10), expressed on autoreactive CD4(hi)panCD44(hi) T cells, are critically involved in the pathogenesis of classic EAE by increasing their life span. Targeting these short CD44(v) isoform regions may reduce inflammatory processes and clinical symptoms in MS.

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PF-03475952: a potent and neutralizing fully human anti-CD44 antibody for therapeutic applications in inflammatory diseases

Abstract: Targeting of CD44 is a unique mechanism of action in the treatment of inflammatory diseases and is expected to reduce joint damage induced by inflammatory mediators, resulting in disease modification in inflammatory diseases such as rheumatoid arthritis.

Cited by 21 publications

References 16 publications

Hyaluronan as a therapeutic target in human diseases

Hyaluronan as a therapeutic target in human diseases

CD44 in hematological neoplasias

CD44 variant isoforms control experimental autoimmune encephalomyelitis by affecting the lifespan of the pathogenic T cells

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