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Dual functional monoclonal antibody PF-04605412 targets integrin alpha5beta1 and elicits potent antibody-dependent cellular cytotoxicity.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Li, Gang Zhang, Lianglin Chen, Enhong Wang, Jianying Jiang, Xin Wei Chen, Jeffrey H. Wickman, Grant Raymond. Amundson, Karin Kristina Bergqvist, Simon Zobel, James F. Buckman, D. Matt Baxi, Sangita M. Bender, Steven Lee Casperson, Gerald Fries Hu-Lowe, Dana D. |
| Copyright Year | 2010 |
| Abstract | Integrin α5β1 is overexpressed in tumor-associated stroma and cancer cells, and has been implicated in angiogenesis, tumor survival, and metastasis. Antibody-dependent cellular cytotoxicity (ADCC) by immune effector cells has been shown to contribute to clinical efficacy for several IgG1 monoclonal antibody (mAb) therapeutics. Taking advantage of these two mechanisms, we generated a fully human, fragment crystalizable (Fc)-engineered IgG1 mAb, PF-04605412 (PF-5412), which specifically neutralizes α5 and binds the Fcγ receptors (FcγR) with enhanced affinity. In vitro, PF-5412 potently inhibited α5β1-mediated intracellular signaling, cell adhesion, migration, and endothelial cell (EC) tubulogenesis. PF-5412 induced significantly greater ADCC in α5-expressing tumor cells and ECs compared with a wild-type IgG1 (IgG1/wt) or IgG2 of identical antigen specificity. The degree of ADCC correlated with the abundance of natural killer (NK) cells in the peripheral blood mononuclear cells but was independent of donor FcγRIIIa polymorphism. In animal studies, PF-5412 displayed robust and dose-dependent antitumor efficacy superior to that observed with IgG1/wt, IgG2, or IgG4 of identical antigen specificity. The degree of efficacy correlated with α5 expression, macrophage and NK cell infiltration, and NK activity in the tumor. Depletion of host macrophages abrogated antitumor activity, suggesting a critical contribution of macrophage-mediated antitumor activity of PF-5412. Combination of PF-5412 with sunitinib significantly improved antitumor efficacy compared with either agent alone. The dual mechanism of action and robust antitumor efficacy of PF-5412 support its clinical development for the treatment of a broad spectrum of human malignancies. |
| Starting Page | 345 |
| Ending Page | 345 |
| Page Count | 1 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://cancerres.aacrjournals.org/content/canres/70/24/10243.full.pdf |
| PubMed reference number | 21159645v1 |
| Alternate Webpage(s) | https://doi.org/10.1158/0008-5472.CAN-10-1996 |
| DOI | 10.1158/0008-5472.CAN-10-1996 |
| Journal | Cancer research |
| Volume Number | 70 |
| Issue Number | 24 |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Affinity Antibody-Dependent Cellular Cytotoxicity Cell Adhesion Cell-Mediated Cytolysis Dual Endothelial Cells Fab Immunoglobulins Fc Receptor Integrin alpha5beta1 Integrins Monoclonal Antibodies Natural killer Neoplasms PF-04605412 Peripheral blood mononuclear cell (cell) Stroma Therapeutic procedure sunitinib |
| Content Type | Text |
| Resource Type | Article |
