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Annals of Oncology : Official Journal... Oct 2013Because metastatic breast cancer (MBC) is incurable in most cases, the goals of treatment are improvement in quality of life, management of symptoms, and prolonged... (Review)
Review
Because metastatic breast cancer (MBC) is incurable in most cases, the goals of treatment are improvement in quality of life, management of symptoms, and prolonged survival. The human epidermal growth factor receptor 2 (HER2) is overexpressed in up to 30% of breast tumors, and before the development of HER-targeted therapy, HER2 positivity was predictive of poorer clinical outcomes. Trastuzumab and pertuzumab (anti-HER2 monoclonal antibodies), lapatinib (a small molecule inhibitor of HER2 and the epidermal growth factor receptor [EGFR]) are approved for treating HER2-positive MBC in the United States. Although trastuzumab plus chemotherapy is currently regarded as the first-line standard of care for HER2-positive MBC, it is not without shortcomings; these include its association with certain adverse events (e.g. cardiotoxic effect) and development of resistance. A number of investigational agents that target HER2 and other members of that receptor family are in clinical development for patients with HER2-positive MBC whose disease has progressed on trastuzumab. In addition, in an effort to overcome treatment resistance, clinical trials are evaluating combination therapy (investigational HER-targeted agents with trastuzumab or lapatinib). This review discusses recently completed and ongoing phase II and III clinical trials of investigational HER-targeted agents in the setting of trastuzumab-progressive, HER2-positive MBC.
Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Lapatinib; Maytansine; Neoadjuvant Therapy; Neoplasm Metastasis; Protein Kinase Inhibitors; Quinazolines; Receptor, ErbB-2; Trastuzumab
PubMed: 23827380
DOI: 10.1093/annonc/mdt217 -
American Society of Clinical Oncology... 2016The natural history of HER2-positive breast cancer has progressively improved since the introduction of the first anti-HER2 directed therapy (trastuzumab). Trastuzumab... (Review)
Review
The natural history of HER2-positive breast cancer has progressively improved since the introduction of the first anti-HER2 directed therapy (trastuzumab). Trastuzumab has significantly increased survival of patients with HER2-positive metastatic breast cancer and, after the standardization of the use of this drug in the adjuvant setting in 2005, has also avoided many disease recurrences and, consequently, saved many lives. Later on, the introduction of lapatinib offered new choices for patients with advanced HER2-positive breast cancer, although the drug has failed to show a clear efficacy in the adjuvant setting. New promising drugs have been approved to broaden the horizon of HER2-positive breast cancer such as pertuzumab or T-DM1, but we need new options to further improve the management of these diseases. In this review, we cover new strategies that are currently under evaluation for the treatment of patients with HER2-positive breast cancer, including new tyrosine kinase inhibitors (neratinib, ONT-380), new antibody-drug conjugates targeting HER2 (MM-302), and new indications of already approved drugs (T-DM1), as well as the potential dual combinations of anti-HER2 therapy with phosphoinositide 3-kinase/mTOR or cell cycle inhibitors (palbociclib, abemaciclib). Last but not least, we briefly review a new paradigm of emerging approaches that involve the host immune response, HER2 breast cancer vaccines, and other immune strategies, including immune checkpoint inhibition.
Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Breast Neoplasms; Cancer Vaccines; Female; Humans; Immunotherapy; Lapatinib; Maytansine; Molecular Targeted Therapy; Neoplasm Recurrence, Local; Protein Kinase Inhibitors; Quinazolines; Receptor, ErbB-2; Trastuzumab
PubMed: 27249772
DOI: 10.1200/EDBK_159167 -
Journal of Nuclear Medicine : Official... Aug 2019Epidermal growth factor receptor I (EGFR) is overexpressed in most cancers of epithelial origin. Antibody drug conjugates (ADCs) with PEGylated-maytansine (PEG-DM1) show...
Epidermal growth factor receptor I (EGFR) is overexpressed in most cancers of epithelial origin. Antibody drug conjugates (ADCs) with PEGylated-maytansine (PEG-DM1) show promise in vitro and in vivo. However, in vivo biodistribution data for ADCs with PEG-DM1 have not been reported. Development of methods to understand the real-time in vivo behavior of these ADCs is needed to move these compounds to the clinic. Here we have used noninvasive small-animal SPECT/CT imaging and ex vivo biodistribution to understand the in vivo behavior of PEG-DM1 ADCs. We developed nimotuzumab ADCs conjugated to PEG-DM1. We generated immunoconjugates with low (nimotuzumab-PEG-DM1-Low) and high (nimotuzumab-PEG-DM1-High) drug-to-antibody ratios. The drug-to-antibody of nimotuzumab-PEG-DM1-Low and nimotuzumab-PEG-DM1-High was 3.5 and 7.3, respectively. Quality control was performed using ultraviolet spectrophotometry, size-exclusion high-performance liquid chromatography, bioanalyzer, biolayer interferometry, and flow cytometry in EGFR-positive DLD-1 cells. These immunoconjugates were conjugated with DOTA and radiolabeled with In. The in vitro binding and internalization rates of In-nimotuzumab, In-nimotuzumab-PEG-DM1-Low, and In-nimotuzumab-PEG-DM1-High were characterized. Furthermore, the pharmacokinetics, biodistribution, and imaging characteristics were evaluated in normal and DLD-1 tumor-bearing mice. Flow cytometry and biolayer interferometry showed a trend toward decreasing EGFR affinity with increasing number of PEG-DM1 on the antibody. Despite the lower overall cellular binding of the PEG-DM1 radioimmunoconjugates, internalization was higher for PEG-DM1 ADCs than for the non-PEGylated ADC in the following order: In-nimotuzumab-PEG-DM1-High > In-nimotuzumab-PEG-DM1-Low > In-nimotuzumab. Nuclear uptake of In-nimotuzumab-PEG-DM1-High was 4.4-fold higher than In-nimotuzumab. Pharmacokinetics and biodistribution showed that In-nimotuzumab-PEG-DM1-High had the slowest blood and whole-body clearance rate. Uptake in DLD-1 tumors of In-nimotuzumab was similar to In-nimotuzumab-PEG-DM1-Low but was significantly higher than for In-nimotuzumab-PEG-DM1-High. Tumor-to-background ratios for In-nimotuzumab and In-nimotuzumab-PEG-DM1-Low were higher than for In-nimotuzumab-PEG-DM1-High. The results show that conjugation of multiple PEG-DM1 reduces the affinity for EGFR in vitro. However, the reduced affinity is counteracted by the high internalization rate of constructs with PEG-DM1 ADCs in vitro. The decreased affinity resulted in low tumor uptake of In-nimotuzumab-PEG-DM1-High, with a slow overall whole-body clearance rate. These data provide insights for evaluating the pharmacokinetics and normal -tissue toxicity and in determining dosing rate of PEGylated ADCs.
Topics: Animals; Antibodies, Monoclonal, Humanized; Cell Line, Tumor; Chromatography, High Pressure Liquid; ErbB Receptors; Flow Cytometry; HT29 Cells; Humans; Immunoconjugates; Indium Radioisotopes; Interferometry; Kinetics; Maytansine; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Neoplasms; Polyethylene Glycols; Single Photon Emission Computed Tomography Computed Tomography; Spectrophotometry, Ultraviolet; Tissue Distribution; Trastuzumab
PubMed: 30655327
DOI: 10.2967/jnumed.118.220095 -
Molecular Cancer Therapeutics Nov 2023Systemic exposure to released cytotoxic payload contributes to the dose-limiting off-target toxicities of anticancer antibody-drug conjugates (ADC). In this work, we...
Systemic exposure to released cytotoxic payload contributes to the dose-limiting off-target toxicities of anticancer antibody-drug conjugates (ADC). In this work, we present an "inverse targeting" strategy to optimize the therapeutic selectivity of maytansinoid-conjugated ADCs. Several anti-maytansinoid sdAbs were generated via phage-display technology with binding IC50 values between 10 and 60 nmol/L. Co-incubation of DM4 with the anti-maytansinoid sdAbs shifted the IC50 value of DM4 up to 250-fold. Tolerability and efficacy of 7E7-DM4 ADC, an anti-CD123 DM4-conjugated ADC, were assessed in healthy and in tumor-bearing mice, with and without co-administration of an anti-DM4 sdAb. Co-administration with anti-DM4 sdAb reduced 7E7-DM4-induced weight loss, where the mean values of percentage weight loss at nadir for mice receiving ADC+saline and ADC+sdAb were 7.9% ± 3% and 3.8% ± 1.3% (P < 0.05). In tumor-bearing mice, co-administration of the anti-maytansinoid sdAb did not negatively affect the efficacy of 7E7-DM4 on tumor growth or survival following dosing of the ADC at 1 mg/kg (P = 0.49) or at 10 mg/kg (P = 0.9). Administration of 7E7-DM4 at 100 mg/kg led to dramatic weight loss, with 80% of treated mice succumbing to toxicity before the appearance of mortality relating to tumor growth in control mice. However, all mice receiving co-dosing of 100 mg/kg 7E7-DM4 with anti-DM4 sdAb were able to tolerate the treatment, which enabled reduction in tumor volume to undetectable levels and to dramatic improvements in survival. In summary, we have demonstrated the utility and feasibility of the application of anti-payload antibody fragments for inverse targeting to improve the selectivity and efficacy of anticancer ADC therapy.
Topics: Animals; Mice; Immunoconjugates; Maytansine; Neoplasms; Therapeutic Index; Weight Loss; Cell Line, Tumor
PubMed: 37493255
DOI: 10.1158/1535-7163.MCT-22-0804 -
Frontiers in Bioscience (Landmark... Jan 2014Lorvotuzumab mertansine (LM) is an ADC composed of an anti CD56 humanized N901 monoclonal antibody conjugated via a stable disulfide linker to the maytansinoid DM1. CD56... (Review)
Review
Lorvotuzumab mertansine (LM) is an ADC composed of an anti CD56 humanized N901 monoclonal antibody conjugated via a stable disulfide linker to the maytansinoid DM1. CD56 is expressed in up to 78% of multiple myelomas. LM displays antitumor activity in preclinical models of multiple myeloma. In a phase I study of MM, the MTD of single-agent LM was 112 mg/m². The dose-limiting toxicities were grade 3 fatigue and grade 3 acute, reversible, renal failure. 2 PRs and 4 MRs were observed at various dose levels starting at 60 mg/m². Building on the single agent experience, a phase II study of LM in combination with lenalidomide and dexamethasone was conducted. The optimal dose of LM was 75 mg/m² in the combination. The ORR was 56.4%. The most common treatment-related AE was peripheral neuropathy (PN), mostly grade 2 or less, with the majority of patients having a grade 1 PN at baseline. Continued evaluation of optimal dosing levels and schedules will be important to better define the utility of this promising treatment.
Topics: Antibodies, Monoclonal; CD56 Antigen; Humans; Immunoconjugates; Maytansine; Multiple Myeloma
PubMed: 24389179
DOI: 10.2741/4202 -
Magyar Onkologia Sep 2013A new trend has been taking place in the daily oncology practice in the past twenty years: we are progressively moving toward individualized and personalized treatments.... (Review)
Review
A new trend has been taking place in the daily oncology practice in the past twenty years: we are progressively moving toward individualized and personalized treatments. The treatment of breast cancer is one of the best examples to underline the outstanding effectiveness of the individualized approach. The modern molecular pathology features are capable of predicting the biological behavior of the tumors which gives a new basis for our therapeutic choices, both for neoadjuvant and adjuvant settings, as well as for metastatic disease. In our paper we review the currently used monoclonal antibodies in the treatment of breast cancer and provide an overview of the new research and future directions in this field.
Topics: Ado-Trastuzumab Emtansine; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Breast Neoplasms; Cetuximab; Chemotherapy, Adjuvant; ErbB Receptors; Female; Heart; Humans; Maytansine; Molecular Targeted Therapy; Neoadjuvant Therapy; Panitumumab; Trastuzumab
PubMed: 24107821
DOI: No ID Found -
MAbs 2022Biotherapeutics are exposed to common transition metal ions such as Cu(II) and Fe(II) during manufacturing processes and storage. IgG1 biotherapeutics are vulnerable to...
Biotherapeutics are exposed to common transition metal ions such as Cu(II) and Fe(II) during manufacturing processes and storage. IgG1 biotherapeutics are vulnerable to reactive oxygen species (ROS) generated via the metal-catalyzed oxidation reactions. Exposure to these metal ions can lead to potential changes to structure and function, ultimately influencing efficacy, potency, and potential immunogenicity of the molecules. Here, we stress four biotherapeutics of the IgG1 subclass (trastuzumab, trastuzumab emtansine, anti-NaPi2b, and anti-NaPi2b-vc-MMAE) with two common pharmaceutically relevant metal-induced oxidizing systems, Cu(II)/ ascorbic acid and Fe(II)/ HO, and evaluated oxidation, size distribution, carbonylation, Fc effector functions, antibody-dependent cellular cytotoxicity (ADCC) activity, cell anti-proliferation and autophaghic flux. Our study demonstrates that the extent of oxidation was metal ion-dependent and site-specific, leading to decreased FcγRIIIa and FcRn receptor binding and subsequently potentially reduced bioactivity, though antigen binding was not affected to a great extent. In general, the monoclonal antibody (mAb) and corresponding antibody-drug conjugate (ADC) showed similar impacts to product quality when exposed to the same metal ion, either Cu(II) or Fe(II). Our study clearly demonstrates that transition metal ion binding to therapeutic IgG1 mAbs and ADCs is not random and that oxidation products show unique structural and functional ramifications. A critical outcome from this study is our highlighting of key process parameters, route of degradation, especially oxidation (metal catalyzed or via ROS), on the CH1 and Fc region of full-length mAbs and ADCs.: DNPH 2,4-dinitrophenylhydrazine; ADC Antibody drug conjugate; ADCC Antibody-dependent cellular cytotoxicity; CDR Complementary determining region; DTT Dithiothreitol; HMWF high molecular weight form; LC-MS Liquid chromatography-mass spectrometry; LMWF low molecular weight forms; MOA Mechanism of action; MCO Metal-catalyzed oxidation; MetO Methionine sulfoxide; mAbs Monoclonal antibodies; MyBPC Myosin binding protein C; ROS Reactive oxygen species; SEC Size exclusion chromatography.
Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Ascorbic Acid; Catalysis; Dithiothreitol; Ferrous Compounds; Hydrogen Peroxide; Immunoconjugates; Immunoglobulin G; Myosins; Oxidation-Reduction; Protein C; Reactive Oxygen Species; Trastuzumab
PubMed: 36151884
DOI: 10.1080/19420862.2022.2122957 -
Journal of Clinical Oncology : Official... Jun 2020This phase I study, which to our knowledge is the first-in-human study of this kind, investigates the safety, tolerability, pharmacokinetics, and clinical activity of...
First-in-Human, Multicenter, Phase I Dose-Escalation and Expansion Study of Anti-Mesothelin Antibody-Drug Conjugate Anetumab Ravtansine in Advanced or Metastatic Solid Tumors.
PURPOSE
This phase I study, which to our knowledge is the first-in-human study of this kind, investigates the safety, tolerability, pharmacokinetics, and clinical activity of anetumab ravtansine, an antibody-drug conjugate of anti-mesothelin antibody linked to maytansinoid DM4, in patients with advanced, metastatic, or recurrent solid tumors known to express the tumor-differentiation antigen mesothelin.
PATIENTS AND METHODS
This phase I, open-label, multicenter, dose-escalation and dose-expansion study of anetumab ravtansine enrolled 148 adult patients with multiple solid tumor types. Ten dose-escalation cohorts of patients with advanced or metastatic solid tumors (0.15-7.5 mg/kg) received anetumab ravtansine once every 3 weeks, and 6 expansion cohorts of patients with advanced, recurrent ovarian cancer or malignant mesothelioma received anetumab ravtansine at the maximum tolerated dose once every 3 weeks, 1.8 mg/kg once per week, and 2.2 mg/kg once per week.
RESULTS
Forty-five patients were enrolled across the 10 dose-escalation cohorts. The maximum tolerated dose of anetumab ravtansine was 6.5 mg/kg once every 3 weeks or 2.2 mg/kg once per week. Thirty-two patients were enrolled in the 6.5 mg/kg once-every-3-weeks, 35 in the 1.8 mg/kg once-per-week, and 36 in the 2.2 mg/kg once-per-week expansion cohorts. The most common drug-related adverse events were fatigue, nausea, diarrhea, anorexia, vomiting, peripheral sensory neuropathy, and keratitis/keratopathy. There were no drug-related deaths. Anetumab ravtansine pharmacokinetics were dose proportional; the average half-life was 5.5 days. Among 148 patients with mesothelioma or ovarian, pancreatic, non-small-cell lung, and breast cancers, 1 had a complete response, 11 had partial responses, and 66 had stable disease. High levels of tumor mesothelin expression were detected in patients with clinical activity.
CONCLUSION
Anetumab ravtansine exhibited a manageable safety and favorable pharmacokinetic profile with encouraging preliminary antitumor activity in heavily pretreated patients with mesothelin-expressing solid tumors. The results allowed for the determination of recommended doses, schedules, and patient populations for anetumab ravtansine in phase II studies.
Topics: Adult; Aged; Antineoplastic Agents, Immunological; Female; GPI-Linked Proteins; Humans; Immunoconjugates; Male; Maximum Tolerated Dose; Maytansine; Mesothelin; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasms; Progression-Free Survival
PubMed: 32213105
DOI: 10.1200/JCO.19.02085 -
Breast Care (Basel, Switzerland) Dec 2017The human epidermal growth factor receptor 2 (HER2) is commonly associated with poor prognosis and is overexpressed in approximately 15-20% of all breast cancers. The... (Review)
Review
The human epidermal growth factor receptor 2 (HER2) is commonly associated with poor prognosis and is overexpressed in approximately 15-20% of all breast cancers. The introduction of HER2-targeted therapies led to significant improvement in the prognosis of patients with HER2-positive breast cancer, for both early and advanced disease. These targeted therapies include the antibodies trastzumab and pertuzumab, the tyrosine kinase inhibitor lapatinib, and the antibody-drug conjugate trastuzumab emtansine (T-DM1). T-DM1 combines the anti-tumor activity of trastuzumab with that of DM1, a highly potent derivative of the anti-microtubule agent maytansine, resulting in increased anti-tumor activity. Notably, this agent has been demonstrated to be safe and is associated with low toxicity rates. However, maytansinoid, the cytotoxic component of T-DM1, does have the potential to induce various adverse events, particularly radiation necrosis, when used in combination with stereotactic radiosurgery. In this review, we aimed to summarize the current literature regarding T-DM1 safety and toxicity, with special emphasis on the existing landmark studies.
PubMed: 29456473
DOI: 10.1159/000480492 -
Journal of Clinical Oncology : Official... Jul 2014To provide evidence-based recommendations to practicing oncologists and others on systemic therapy for patients with human epidermal growth factor receptor 2 (HER2)... (Review)
Review
Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology clinical practice guideline.
PURPOSE
To provide evidence-based recommendations to practicing oncologists and others on systemic therapy for patients with human epidermal growth factor receptor 2 (HER2) -positive advanced breast cancer.
METHODS
The American Society of Clinical Oncology convened a panel of medical oncology, radiation oncology, guideline implementation, and advocacy experts and conducted a systematic literature review from January 2009 to October 2012. Outcomes of interest included overall survival, progression-free survival (PFS), and adverse events.
RESULTS
A total of 16 trials met the systematic review criteria. The CLEOPATRA trial found survival and PFS benefits for docetaxel, trastuzumab, and pertuzumab in first-line treatment, and the EMILIA trial found survival and PFS benefits for trastuzumab emtansine (T-DM1) in second-line treatment. T-DM1 also showed a third-line PFS benefit. One trial reported on duration of HER2-targeted therapy, and three others reported on endocrine therapy for patients with HER-positive advanced breast cancer.
RECOMMENDATIONS
HER2-targeted therapy is recommended for patients with HER2-positive advanced breast cancer, except for those with clinical congestive heart failure or significantly compromised left ventricular ejection fraction, who should be evaluated on a case-by-case basis. Trastuzumab, pertuzumab, and taxane for first-line treatment and T-DM1 for second-line treatment are recommended. In the third-line setting, clinicians should offer other HER2-targeted therapy combinations or T-DM1 (if not previously administered) and may offer pertuzumab, if the patient has not previously received it. Optimal duration of chemotherapy is at least 4 to 6 months or until maximum response, depending on toxicity and in the absence of progression. HER2-targeted therapy can continue until time of progression or unacceptable toxicities. For patients with HER2-positive and estrogen receptor-positive/progesterone receptor-positive breast cancer, clinicians may recommend either standard first-line therapy or, for selected patients, endocrine therapy plus HER2-targeted therapy or endocrine therapy alone.
Topics: Ado-Trastuzumab Emtansine; Anastrozole; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Clinical Trials as Topic; Comorbidity; Docetaxel; Drug Administration Schedule; Evidence-Based Medicine; Female; Health Status Disparities; Healthcare Disparities; Humans; Lapatinib; Letrozole; Maytansine; Molecular Targeted Therapy; Nitriles; Quinazolines; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone; Societies, Medical; Taxoids; Trastuzumab; Treatment Outcome; Triazoles; United States
PubMed: 24799465
DOI: 10.1200/JCO.2013.54.0948