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Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Antibodies and toxins as well as a combination of both, the antibody-drug conjugates (ADCs), are among others used for an aimed interaction with specific cancer cells resulting in apoptosis. Their action relies on inducing DNA breaks or on binding to microtubules playing important roles in eukaryotic cells including cell proliferation, trafficking, signaling, and migration (Dumontet and Jordan, 2010). The preparation of ADCs comprises the choice of a suited target antigen, the isolation and characterization of potent toxins and the development of stable linkers between Ab and toxin that guarantee a release of the toxin only after the ADC is internalized (Dingermann and Zündorf, 2014). An example is shown in the opposite scheme with the ADC trastuzumab emtansine where the highly cytotoxic maytansine, a 19-membered lactam, with an additional sulfhydryl group is bound via the SMCC (succinimidyl trans-4-(N-maleimidomethyl)cyclohexane-1-carboxylate) crosslinker to the mAb that was developed by Genentech for women with inoperable, locally advanced or metastatic HER2-positive breast cancer. Whereas trastuzumab alone stops growth of cancer cells by binding to the HER2/neu receptor, emtansine enters cells and destroys them by binding to microtubules. For reviews on monoclonal antibodies in cancer therapy see, e.g., Scott (2012, 2012a), Baldo (2016), Ndoja and Lima (2017).
Role of Engineered Proteins as Therapeutic Formulations
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Khushboo Gulati, Krishna Mohan Poluri
Ado-trastuzumab emtansine (Kadcyla) and brentuximab vedotin (Adcetris) are two ADCs that are being used for the treatment of hematological malignancies (Hodgkin lymphoma) and solid tumor (breast cancer), respectively (Beck and Reichert, 2014; Scott, 2017a). Brentuximab vedotin is a conjugate of a monoclonal antibody targeting CD30, which is expressed only during Hodgkin lymphoma. It is connected via cathepsin to anti-mitotic drug monomethyl auristatin E (Beck and Reichert, 2014; Scott, 2017a). Ado-trastuzumab emtansine is composed of anti-Her2-mAb Trastuzumab antibody linked to cytotoxic drug mertansine via thioether linkage (Beck and Reichert, 2014; Lambert and Chari, 2014). Variety of drugs can be conjugated at multiple locations in monoclonal antibody to further enhance their actions (Tobin et al., 2014).
Precision medicine in oncology: An overview
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
Fazilet Yılmaz, Sultan Ciftci Yılmaz, Esra Gunduz, Mehmet Gunduz
Breast cancer drugs Herceptin (trastuzumab), Perjeta (pertuzumab), and Kadcyla (ado-trastuzumab emtansine) also work with the same approach. They target HER2, an oncogene activated in some breast cancer (FDA, 2016b).
Cost-efficiency analysis of conversion to biosimilar filgrastim for supportive cancer care and resultant expanded access analysis to supportive care and early-stage HER2+ breast cancer treatment in Saudi Arabia: simulation study
Published in Journal of Medical Economics, 2023
Consuela Cheriece Yousef, Mansoor Ahmed Khan, Hind Almodaimegh, Majed Alshamrani, Meteb Al-Foheidi, Hana AlAbdalkarim, Ahmed AlJedai, Anjum Naeem, Ivo Abraham
All prices were obtained from NUPCO as a benchmark and reflect the true healthcare expenditures in the public sector in regards to medication costs.35 Calculations were in US dollars. The NUPCO pack price was converted into US dollars using the fixed international exchange rate of 3.75 Saudi Arabian Riyals to 1 USD$.36 Using NUPCO prices shown in Table 1, we calculated the potential cost saving impact by assuming substitution of reference G-CSF with its biosimilars at the national level. The revenue and potential saving generated from this switching exercise were used to expand access on a budget-neutral basis to prophylaxis with biosimilar filgrastim or ado-trastuzumab emtansine, as specified above. Additionally, we analyzed how the potential savings lead to expanded access to further supportive care with biosimilar G-CSF. The basis for these analyses is the assumption that cost-savings from the use of biosimilars are re-allocated on a budget-neutral basis to provide access to either therapeutic or supportive cancer care to more patients. Therapeutic care was defined as ado-trastuzumab emtansine 260 mg every 3 weeks for 14 doses. Supportive care was defined as six cycles of prophylaxis with biosimilar G-CSF using five injections per cycle.
Apoferritin: a potential nanocarrier for cancer imaging and drug delivery
Published in Expert Review of Anticancer Therapy, 2021
Hanitrarimalala Veroniaina, Xiuhua Pan, Zhenghong Wu, Xiaole Qi
Cancer stem cells (CSCs) are multiple heterogeneous cell types, most of which originate from tumor cells, metastasis, and drug resistance due to their self-renewal ability [68,69]. The properties of these cells remain a major challenge in cancer therapy because conventional treatments, including chemotherapy and radiotherapy, are unable to eliminate the CSCs resulting in tumor recurrence [70]. Additionally, the diversity of CSCs types makes cancer therapy difficult. Combined therapeutic systems have been used to kill CSCs [71], but the investigations have been restricted due to the unspecific binding of the system, which has eliminated both CSCs and healthy cells. More researchers have therefore been interested in developing CSCs-targeted therapeutic approaches. Specifically, Siling’s group formulated apoferritin-loading mertansine nanocages that were successfully recognized and internalized by CSCs that induced significant eradication of CSCs in 3D tumorspheres [27]. The results of this research promised the use of apoferritin as a nanoplatform to eliminate CSCs for effective anti-cancer therapy.
Immunotherapy as a partner for HER2-directed therapies
Published in Expert Review of Anticancer Therapy, 2021
Guy T Clifton, and George E Peoples
Trastuzumab emtansine is an antibody drug conjugate that links the trastuzumab antibody with the potent microtubule-targeting cytotoxic compound, emtansine. Trastuzumab emtansine works by retaining the anticancer effects of trastuzumab along with intracellular delivery of emtansine, a drug which has an unacceptably high therapeutic index when given systemically unbound [34]. Trastuzumab emtansine is used for the treatment of metastatic breast cancer after prior treatment with trastuzumab or as adjuvant therapy in patients with residual disease after neoadjuvant therapy with trastuzumab and a taxane [35]. It is not known if the conjugation of emtansine impacts the immunologic effects of trastuzumab; however, there is evidence that maytansinoid drugs, like emtansine, promote T-cell responses by inducing dendritic cell maturation [36]. The combination of trastuzumab emtansine with CTLA-4 and PD-1 inhibitors was synergistic against a HER2-overexpressing preclinical model [37].