Novel monoclonal antibody against beta 1 integrin enhances cisplatin efficacy in human lung adenocarcinoma cells

Abstract

The use of anti-beta 1 integrin monoclonal antibody in lung cancer treatment has proven beneficial. Here, we developed a novel monoclonal antibody (mAb), called P5, by immunizing mice with human peripheral blood mononuclear cells (PBMC). Its anti-tumor effect is now being tested, in a clinical phase III trial, in combinatorial treatments with various chemical drugs. To confirm that P5 indeed binds to beta 1 integrin, cell lysates were immunoprecipitated with commercial anti-beta 1 integrin mAb (TS2/16) and immunoblotted against P5 to reveal a 140 kDa molecular weight band, as expected. Immunoprecipitation with P5 followed by LC/MS protein sequence analysis further verified P5 antigen to be beta 1 integrin. Cisplatin treatment upregulated cell surface expression of beta 1 integrin in A549 cells, while causing inhibition of cell growth. When cells were co-treated with different concentrations of P5 mAb, the cisplatin-mediated inhibitory effect was enhanced in a dose-dependent manner. Our findings show that a combinatorial treatment of P5 mAb and cisplatin in A549 cells resulted in a 30% increase in apoptosis, compared to baseline, and significantly more when compared to either the cisplatin or P5 alone group. The entire peptide sequences in CDR from variable region of Ig heavy and light chain gene for P5 mAb are also disclosed. Together, these results provide evidence of the beneficial effect of P5 mAb in combinatorial treatment of human lung adenocarcinoma.

Integrin α2β1 Represents a Prognostic and Predictive Biomarker in Primary Ovarian Cancer

“…Phase II studies are ongoing to evaluate the combination with chemotherapy in colon carcinoma (NCT01347645, NCT01133990, NCT00309179). Another β1-antibody could improve the efficiency of platinum-based chemotherapy in non-small-cell lung cancer [ 56 ]. However, despite these promising approaches, the complex biology of heterodimers with promiscuous ligands, allosteric activation, and multiple intracellular signaling pathways might hinder successful treatment strategies [ 13 , 57 , 58 ].…”

Integrins as Therapeutic Targets: Successes and Cancers

“…A pan- β1 murine monoclonal antibody, P5 (Chungbuk University (Cheongju, Korea)), claimed to predominantly act at α5β1, is reported in PH3 trials for NSCLC [ 106 ]. Development on the small molecule α5β1/pan-αv inhibitor GLPG-0187 (Galapagos (Mechelen, Belgium)) appears to have been stopped [ 107 ].…”

“…However, it appears from preclinical models that these integrins may both promote and inhibit tumor development, depending on tumor type and stage [ 157 ]. At present no drug development project specifically targeting the laminin receptors has reached clinical trials, ignoring the pan-specific anti-β1 antibody, P5 [ 106 ].…”

Current Advance of Therapeutic Agents in Clinical Trials Potentially Targeting Tumor Plasticity

“…A novel mAb P5 , which targets CD49e/CD29, is currently being tested in phase III clinical trials to evaluate its anti-tumor effect, but there are only a few reports about its progress of new clinical trials (32). As a FK506 binding protein like (FKBPL) peptide derivative, ALM-201 can bind to CD44 and inhibit cancer related pathways, such as DLL4/NOTCH signal pathway as well as inhibit cell migration, tubule formation and angiogenesis.…”