Pertuzumab

About: Pertuzumab is a research topic. Over the lifetime, 1453 publications have been published within this topic receiving 73219 citations. The topic is also known as: 2C4 Antibody & MOAB 2C4.

Targeting HER2 for the Treatment of Breast Cancer

Abstract: HER2 (ErbB2), a member of the HER family of tyrosine kinase receptors (HER1–4), is a major driver of tumor growth in 20% of breast cancers. Treatment with the anti-HER2 monoclonal antibody trastuzumab has revolutionized the outcome of patients with this aggressive breast cancer subtype, but intrinsic and acquired resistance is common. Growing understanding of the biology and complexity of the HER2 signaling network and of potential resistance mechanisms has guided the development of new HER2-targeted agents. Combinations of these drugs to more completely inhibit the HER receptor layer, or combining HER2-targeted agents with agents that target downstream signaling, alternative pathways, or components of the host immune system, are being vigorously investigated in the preclinical and clinical settings. As a result, the list of more effective and well tolerated FDA-approved new regimens for patients with HER2+ tumors is constantly growing.

Treatment of Human Epidermal Growth Factor Receptor 2–Overexpressing Breast Cancer Xenografts With Multiagent HER-Targeted Therapy

Abstract: BACKGROUND Human epidermal growth factor receptor 2 (HER2) is a member of the HER signaling pathway. HER inhibitors partially block HER signaling and tumor growth in preclinical breast cancer models. We investigated whether blockade of all HER homo- and heterodimer pairs by combined treatment with several inhibitors could more effectively inhibit tumor growth in such models. METHODS Mice carrying xenograft tumors of HER2-overexpressing MCF7/HER2-18 (HER2-transfected) or BT474 (HER2-amplified) cells were treated with estrogen supplementation or estrogen withdrawal, alone or combined with tamoxifen. One to three HER inhibitors (pertuzumab, trastuzumab, or gefitinib) could also be added (n > or = 8 mice per group). Tumor volumes, HER signaling, and tumor cell proliferation and apoptosis were assessed. Results were analyzed with the t test or Wilcoxon rank sum test and survival analysis methods. All statistical tests were two-sided. RESULTS Median time to tumor progression was 21 days for mice receiving estrogen and 28 days for mice receiving estrogen and pertuzumab (difference = 7 days; P = .001; hazard ratio [HR] of progression in mice receiving estrogen and pertuzumab versus mice receiving estrogen = 0.27, 95% confidence interval [CI] = 0.09 to 0.77). Addition of gefitinib and trastuzumab to estrogen and pertuzumab increased this time to 49 days (difference = 21 days; P = .004; HR of progression = 0.28, 95% CI = 0.10 to 0.76). MCF7/HER2-18 tumors disappeared completely and did not progress (for > or = 189 days) after combination treatment with pertuzumab, trastuzumab, and gefitinib plus tamoxifen (19 of 20 mice) or plus estrogen withdrawal (14 of 15 mice). Both combination treatments induced apoptosis and blocked HER signaling and proliferation in tumor cells better than any single agent or dual combination. All BT474 tumors treated with pertuzumab, trastuzumab, and gefitinib disappeared rapidly, regardless of endocrine therapy, and no tumor progression was observed for 232 days. CONCLUSION Combined treatment with gefitinib, trastuzumab, and pertuzumab to block signals from all HER homo- and heterodimers inhibited growth of HER2-overexpressing xenografts statistically significantly better than single agents and dual combinations.

Structural basis for high-affinity HER2 receptor binding by an engineered protein

Abstract: The human epidermal growth factor receptor 2 (HER2) is specifically overexpressed in tumors of several cancers, including an aggressive form of breast cancer. It is therefore a target for both cancer diagnostics and therapy. The 58 amino acid residue Zher2 affibody molecule was previously engineered as a high-affinity binder of HER2. Here we determined the structure of Zher2 in solution and the crystal structure of Zher2 in complex with the HER2 extracellular domain. Zher2 binds to a conformational epitope on HER2 that is distant from those recognized by the therapeutic antibodies trastuzumab and pertuzumab. Its small size and lack of interference may provide Zher2 with advantages for diagnostic use or even for delivery of therapeutic agents to HER2-expressing tumors when trastuzumab or pertuzumab are already employed. Biophysical characterization shows that Zher2 is thermodynamically stable in the folded state yet undergoing conformational interconversion on a submillisecond time scale. The data suggest that it is the HER2-binding conformation that is formed transiently prior to binding. Still, binding is very strong with a dissociation constant KD = 22 pM, and perfect conformational homogeneity is therefore not necessarily required in engineered binding proteins. A comparison of the original Z domain scaffold to free and bound Zher2 structures reveals how high-affinity binding has evolved during selection and affinity maturation and suggests how a compromise between binding surface optimization and stability and dynamics of the unbound state has been reached.