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.

Abstract P4-21-18: Pre-clinical antitumor activity, tumor localization, and pharmacokinetics of MP0274, an apoptosis inducing, biparatopic HER2-targeting DARPin®

Abstract: Background: HER2 positivity is an important predictive factor for treatment with anti-HER2 agents in several cancers. However, currently available monoclonal antibody and tyrosine kinase inhibitor drugs rarely achieve full disease control. We have developed a new HER2-targeting molecule with a unique pro-apoptotic mode of action that may provide additional benefit to patients. The DARPin® MP0274* binds to two distinct non-overlapping HER2 epitopes and to human serum albumin for half-life extension. As previously shown**, in vitro, MP0274 induces apoptosis and inhibits proliferation of cells expressing HER2 (IHC3+, IHC2+ and IHC1+) and potently inhibits HER2/HER3 downstream signaling. To support clinical development of MP0274, we tested the potency of MP0274 in several HER2 expressing patient-derived xenograft (PDX) models and investigated tumor localization. In addition, pharmacokinetics (PK) analysis was performed in cynomolgus monkeys. Methods: Antitumor activity of MP0274 was tested in breast and gastric HER2 expressing PDX mouse models and was compared to standard of care therapies. Tumor localization of MP0274 was studied using an Indium-111 labeled version of MP0274 in a human ovarian adenocarcinoma (SKOV-3) xenograft model by whole-body SPECT/CT imaging. The PK of MP0274 was studied in cynomolgus monkeys (MP0274 is cross-reactive with cynomolgus HER2). Results: In breast and gastric cancer PDX models, MP0274 showed superior efficacy compared to trastuzumab and lapatinib and equivalent efficacy compared to trastuzumab plus pertuzumab as measured by relative tumor volume. The imaging study with SPECT/CT demonstrated that MP0274 localizes effectively to the HER2-expressing human tumor within 24 h. The PK study in cynomolgus monkeys showed a half-life of ≥5 days at doses of 5 and 10 mg/kg while at the lowest dose tested (1 mg/kg) MP0274 had a terminal half-life of 0.4 days. The PK results are indicative of target-mediated clearance that becomes saturated at doses above 1 mg/kg. Conclusions: MP0274, with its unique pro-apoptotic mode of action, demonstrates excellent activity in preclinical PDX models, fast localization to tumor and a long half-life in cynomolgus monkeys. MP0274 was well tolerated in all studies. These results suggest that MP0274 has the potential to provide additional clinical benefit to patients with HER2-expressing tumors. A GLP repeated dose toxicology study is ongoing and a phase I clinical trial is in preparation. * DARPins are small repeat proteins, designed to bind targets with high affinity and specificity, which can be combined in a modular fashion to produce multi-functional agents. ** U. Fiedler et al. SABC 2013. Abstract# 1094 & Poster# P4-12-30. Citation Format: Fiedler U, Metz C, Zitt C, Bessey R, Behe M, Blanc A, Schibli R, Dolado I, Herbst J, Dawson KM, Kiemle-Kallee J. Pre-clinical antitumor activity, tumor localization, and pharmacokinetics of MP0274, an apoptosis inducing, biparatopic HER2-targeting DARPin® [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-18.

Event-Free Survival in Patients with Early HER2-Positive Breast Cancer with a Pathological Complete Response after HER2-Targeted Therapy: A Pooled Analysis

Abstract: Simple Summary The current standard of care for patients with HER2-positive early breast cancer who have a pathological complete response after neoadjuvant HER2-targeted therapy plus chemotherapy is continuation of HER2-targeted therapy in the adjuvant setting. However, it is not clear how long-term outcomes differ by the HER2-targeted regimen received in each setting. To investigate this question, we pooled patient-level data (n = 1763) from neoadjuvant studies of trastuzumab and pertuzumab to evaluate outcomes with respect to single versus dual HER2 targeting in the neoadjuvant and adjuvant settings. Patients treated with dual HER2-targeted therapy in both the neoadjuvant and adjuvant settings had the highest 4-year event-free survival rates, suggesting that this treatment approach may provide the most benefit for patients with HER2-positive early breast cancer. Abstract The standard-of-care for patients with pathological complete response (pCR) after neoadjuvant human epidermal growth factor receptor 2 (HER2)-targeted therapy plus chemotherapy is continuation of HER2-targeted therapy in the adjuvant setting. Our objective was to evaluate risk of recurrence or death in these patients and determine if outcomes differed by the HER2-targeted regimen received in each setting. We analyzed patient-level data from five randomized trials evaluating trastuzumab, pertuzumab, or both as part of systemic neoadjuvant and adjuvant therapy for HER2-positive early breast cancer, and assessed event-free survival (EFS) in 1763 patients. Patients with pCR had decreased risk of an EFS event versus those with residual disease (unadjusted hazard ratio [HR] = 0.35; 95% confidence interval [CI]: 0.27–0.46). Regardless of pCR status, after adjusting for baseline factors, reduction in EFS event risk was greater in patients administered pertuzumab/trastuzumab in both settings versus those administered only trastuzumab in both settings (HR = 0.36; 95% CI: 0.26–0.49), or pertuzumab/trastuzumab in the neoadjuvant setting and only trastuzumab in the adjuvant setting (HR = 0.67; 95% CI: 0.47–0.96). Patients with pCR had longer EFS than those with residual disease. Patients treated with pertuzumab/trastuzumab in both the neoadjuvant and adjuvant settings had the lowest risk of breast cancer recurrence.

Abstract LB-261: Mechanism of action of MCLA-128, a humanized bispecific IgG1 antibody targeting the HER2:HER3 heterodimer

Abstract: Background: MCLA-128 is an ADCC-enhanced humanized common light chain bispecific IgG1 antibody that targets the HER2:HER3 dimer with nanomolar affinity, potently inhibiting tumor growth in vitro and in vivo . MCLA-128 shows superior activity to the combination trastuzumab/ pertuzumab and HER3 targeting monoclonal antibodies and is currently being evaluated in a Phase I clinical trial. This study investigated the mechanism of action of MCLA-128. Methods: Phosphorylation of HER receptors and downstream signaling molecules was studied in vitro and in vivo on HER2-amplified cancer cell lines by Pathscan arrays, luminex beads and Western blot analysis. Inhibition of MCLA-128 cell growth in combination with tyrosine kinase inhibitors and small molecules targeting the MAPK and PI3 kinase/Akt pathway was determined by proliferation inhibition and high content imaging assays. The potential effect of MCLA-128 on primary cardiomyocytes in the presence of Doxorubicin was analyzed by measuring ATP. Binding of MCLA-128 to a panel of cell lines in comparison to HER2 and HER3 antibodies was determined by FACS. Results: In contrast to other HER2 and HER3 targeted agents, only MCLA-128 inhibited phosphorylation of HER3 and downstream Akt and ERK in HER2 amplified cell lines cultured with high concentrations of heregulin in vitro . In xenograft studies, growth inhibition of the trastuzumab-resistant cell line JIMT-1 by MCLA-128 was correlated with reduced HER2:HER3 dimerization and a profound inhibition of the PI3K pathway. Synergistic growth inhibition i n vitro was observed when tyrosine kinase inhibitors or inhibitors of the PI3K pathway were added to HER2 amplified cancer cells in the presence of MCLA-128. MCLA-128 did not show any evidence of cardiotoxicity in vitro in contrast to trastuzumab. MCLA-128 binds and coats breast cancer cell lines with differing levels of HER2 expression more efficiently in comparison to monospecific HER2 or HER3 monoclonal antibodies. Conclusions: The unique simultaneous targeting of MCLA-128 to HER2 and HER3 on HER2-overexpressing breast cancer cells leads to severe impairment of PI3K signaling and reduced cell growth whereas proliferation of primary cardiomyocytes is unaffected. The enhanced coating effect of MCLA-128 also supports its ADCC activity. Citation Format: Cecile Geuijen, Eric Rovers, Tristan Gallenne, David Maussang-Detaille, Arjen Kramer, Nellie Nieuwenhuizen, Carina Clements, Katinka van Zoest, Roy Nijhuis, Therese Visser, Renate Den Blanken-Smit, Willem Bartelink, Vanessa Zondag-van der Zande, Linda Kaldenberg, Pieter-Fokko van Loo, Rob Roovers, Robert Doornbos, Leo Price, Stefan Braam, Setareh van Driel, Lex Bakker, Ton Logtenberg, John de Kruif, Mark Throsby. Mechanism of action of MCLA-128, a humanized bispecific IgG1 antibody targeting the HER2:HER3 heterodimer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-261. doi:10.1158/1538-7445.AM2015-LB-261

HER-2-Positive Ampullary Adenocarcinoma: A Case Report.

Abstract: Background: Ampullary adenocarcinomas are a rare subset of periampullary tumors with an overall poor prognosis. Treatment decisions are generally extrapolated from pancreatic chemotherapy protocols and consist mainly of traditional chemotherapy drugs. There are no known targets for therapeutic intervention in ampullary adenocarcinoma at this time. Next generation sequencing and other novel molecular profiling of tumors, including circulating tumor DNA (ctDNA), have recently made it possible to better understand tumor biology and elucidate driver mutations which are amenable to targeted therapy. This case describes the use of novel DNA sequencing technology to provide a targeted treatment option, HER-2 inhibition, in a patient with HER-2 overexpressing ampullary adenocarcinoma. This is the first time this has been described in the literature. Case presentation: The patient is a 63-year-old Caucasian man who initially presented with symptoms of obstructive jaundice and was found to have a periampullary tumor. He underwent resection of his tumor and pathology confirmed a stage IIB ampullary adenocarcinoma. He unfortunately developed a recurrence in the liver and lung two years later. Next generation sequencing of his tumor at the time of resection as well as ctDNA analysis demonstrated a HER-2 overexpressing tumor. Following first line therapy with FOLFOX he had progression and was treated with trastuzumab and pertuzumab with stabilization of his disease prior to his ultimate demise from multifocal pneumonia. Conclusion: The use of next generation sequencing as well as ctDNA technology generated a novel therapeutic intervention in our patient. As these techniques become more widespread, it is likely more targeted therapies will be used in these difficult to treat diseases.

Subcutaneous her2 antibody formulations

Abstract: Fixed dose HER2 antibody formulations for subcutaneous administration are provided along with their use in the treatment of cancer. The formulations include fixed dose subcutaneous formulations of pertuzumab and subcutaneous co-formulations of pertuzumab and trastuzumab, and their use in the treatment of cancer.