Topic
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.
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TL;DR: In this article , a multi-dimensional liquid chromatography coupled to tandem mass spectrometry method for antibody homo- versus hetero-aggregate characterization is described, and the results demonstrate the high stability of the co-formulation, where only minor aggregate formation is observed upon product storage and accelerated temperature or light-stress conditions.
Abstract: Antibody combination therapies have become viable therapeutic treatment options for certain severe diseases such as cancer. The co-formulation production approach is intrinsically associated with more complex drug product variant profiles and creates more challenges for analytical control of drug product quality. In addition to various individual quality attributes, those arising from the interactions between the antibodies also potentially emerge through co-formulation. In this study, we describe the development of a widely applicable multi-dimensional liquid chromatography coupled to tandem mass spectrometry method for antibody homo- versus hetero-aggregate characterization. The co-formulation of trastuzumab and pertuzumab was used, a challenging model system, comprising two monoclonal antibodies with very similar physicochemical properties. The data presented demonstrate the high stability of the co-formulation, where only minor aggregate formation is observed upon product storage and accelerated temperature or light-stress conditions. The results also show that the homo- and hetero-aggregates, formed in low and comparable proportions, are only marginally impacted by the formulation and product storage conditions. No preferential formation of hetero-aggregates, in comparison to the already existing pertuzumab and trastuzumab homo-aggregates, was observed.
2 citations
TL;DR: Prior receipt of NAT was associated with inferior median PFS following first-line HER2-based therapy in the metastatic setting, however, prior NAT exposure did not significantly impact OS, supporting the efficacy of taxane, trastuzumab, pertuzumAB combination for first- line HER2+ MBC regardless of prior NAT Exposure.
Abstract: Trastuzumab, pertuzumab, and docetaxel are the standard first-line therapy for HER2-positive (HER2+) metastatic breast cancer (MBC). However, only 10% of patients received neoadjuvant and/or adjuvant trastuzumab (NAT) in the registration trial (NCT00567190). In contemporary practice, the majority of recurrent HER2+ MBC patients had prior NAT. We explore any impact of prior therapy on the efficacy of dual HER2-targeted antibody with taxane therapy for metastatic disease. Utilising a prospective national registry, clinico-pathological, treatment, and outcome data for HER2+ MBC patients diagnosed between October 2006 and January 2019 were collected. Survival was estimated by the Kaplan–Meier method and compared among groups by log-rank test. Of 287 HER2+ MBC patients, 222 (77%) received first-line trastuzumab, pertuzumab, and taxane therapy. There were 130 (45%) with de novo MBC. Of the recurrent MBC patients 107/157 (68%) had received NAT. The median progression-free survival (PFS) among patients who received NAT was 15.8 months compared with 24.3 months without prior NAT (hazard ratio [HR] 1.45, 95% CI 1.05–2.03, p = 0.03). The median overall survival (OS) was 42.7 months in patients who had NAT, and was not reached in those who did not (HR 1.80, 95% CI 1.12–2.90, p = 0.02). However, when excluding de novo MBC patients, prior NAT exposure was no longer significantly associated with survival (p = 0.11). De novo MBC patients had the longest median PFS (25.2 months) and OS (91.2 months). Prior receipt of NAT was associated with inferior median PFS following first-line HER2-based therapy in the metastatic setting. However, prior NAT exposure did not significantly impact OS, supporting the efficacy of taxane, trastuzumab, pertuzumab combination for first-line HER2+ MBC regardless of prior NAT exposure. Patients with de novo MBC had the longest survival, suggesting stratification for synchronous versus metachronous disease in prospective clinical trials of MBC should be considered.
2 citations
TL;DR: Results indicate that the HER3 targeting nanoparticle, HerDox, efficiently targets and kills cancer cells that have become resistant to trastuzumab, and has the potential to be used either as a single drug or as part of a combinatorial therapy in eliminating drug-resistant HER2+ breast cancers.
Abstract: HER2-positive breast cancers represent almost a quarter of invasive breast cancers and are indicative of poor patient survival. Although many patients with HER2-positive breast cancer initially respond to anti-HER2 treatments, such as trastuzumab, a significant portion of them develop resistance to these therapies. Consequently, there is a great need to develop new drugs that are effective against these HER2+ tumors that are non-responsive or have become resistant to these therapies. Recently, it has been shown that another member of the HER family, HER3, is commonly upregulated in these drug-resistant cancers. This observation led us to develop a novel drug delivery protein, called HerPBK10, that specifically targets another member of the HER receptor family, HER3. HerPBK10, once it has bound to the HER3 receptor, triggers rapid endocytosis and endosomal penetration, enabling it to deliver a toxic payload to the cell, resulting in cell death. We hypothesized that cytotoxic drugs delivered by HerPBK10 would induce significant targeted cell death in trastuzumab-resistant HER2+ breast cancers due to the high levels of surface HER3 and would therefore provide an effective treatment for patients who have developed resistance to traditional therapies. First, we verified that cell surface levels of HER3 are elevated in trastuzumab-resistant cell lines compared to trastuzumab-sensitive cells. We then demonstrated, through competitive inhibition with free HER3 ligand, that HerPBK10 binds specifically to HER3 on multiple HER2+ cell lines. We assembled our targeted molecule, HerPBK10 with the chemotherapeutic doxorubicin. The resulting nanoparticle, called HerDox, was used to treat HER2+ breast cancer cell lines that were either inherently resistant to trastuzumab or had acquired resistance to trastuzumab. We demonstrated that HerDox caused significant cell death in both types of resistant cells. We also compared the effect of the HerDox nanoparticle to trastuzumab, pertuzumab, and the two drugs together and showed that it caused superior cell death in all three instances. In addition, we combined our nanoparticle with trastuzumab, and showed that together, they have an additive effect on cell death. These results indicate that our HER3 targeting nanoparticle, HerDox, efficiently targets and kills cancer cells that have become resistant to trastuzumab, and has the potential to be used either as a single drug or as part of a combinatorial therapy in eliminating drug-resistant HER2+ breast cancers. We are in the process of verifying these findings in vivo in order to demonstrate the potential of HerDox as a treatment for patients who have become non-responsive to traditional anti-HER2 therapies. Citation Format: Jessica Sims, Michael Taguaim, Chris Hanson, Xiaojiang Cui, Lali K. Medina-Kauwe. Targeting trastuzumab-resistant HER2+ breast cancer with a HER3-targeting nanoparticle. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4487. doi:10.1158/1538-7445.AM2014-4487
2 citations
2 citations