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Current Opinion in Obstetrics &... Feb 2021Antibody-drug conjugates (ADCs) represent a new class of drugs that combine a surface receptor-targeting antibody linked to a cytotoxic molecule. This review summarizes... (Review)
Review
PURPOSE OF REVIEW
Antibody-drug conjugates (ADCs) represent a new class of drugs that combine a surface receptor-targeting antibody linked to a cytotoxic molecule. This review summarizes the current literature demonstrating their tremendous promise as therapeutic agents in the treatment of aggressive gynecologic malignancies.
RECENT FINDINGS
Several antigens have proven to be differentially overexpressed in a variety of gynecologic tumors when compared with normal surrounding tissue and serve as novel targets for ADC therapy. In the last few years HER2/neu, folic acid-alpha (FRα) and Trop-2 overexpression have been exploited as excellent targets by novel ADCs such as Trastuzumab emtansine (T-DM1), SYD985, IMGN853 (Mirvetuximab soravtansine) and Sacituzumab govitecan (SG, IMMU-132) in multiple tumors including ovarian, endometrial and cervical cancers. Although the selectivity of ADCs with noncleavable linkers (i.e. T-DM1) has shown negligible effect on surrounding antigen negative cells, those ADCs with cleavable linkers (i.e. SYD985, IMGN853 and SG) may kill both antigen-positive target cells and surrounding antigen-negative cells via the bystander effect.
SUMMARY
Preclinical data strongly supports these ADCs and ongoing clinical trials will shed further light into the potential of making these drugs part of current standard practice and providing our patients with a higher level of personalized cancer care.
Topics: Ado-Trastuzumab Emtansine; Cell Line, Tumor; Female; Genital Neoplasms, Female; Humans; Immunoconjugates; Trastuzumab
PubMed: 32618744
DOI: 10.1097/GCO.0000000000000642 -
Cancer Dec 2018Significant advances have occurred in the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer that have changed its natural history. The... (Review)
Review
Significant advances have occurred in the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer that have changed its natural history. The addition of trastuzumab to standard therapy has dramatically improved the prognosis for patients with early stage, HER2-positive breast cancer to unprecedented survival outcomes. Yet, long-term follow-up data from adjuvant pivotal trials indicate that 15-24% of patients still develop recurrent disease. Most of the research has focused on the addition of novel anti-HER2 drugs to standard therapy, including studies evaluating the monoclonal antibody pertuzumab; the antibody-drug conjugate trastuzumab-emtansine (T-DM1); the selective, reversible HER2/epidermal growth factor receptor kinase inhibitor lapatinib; or the irreversible pan-HER2 inhibitor neratinib. Dual HER2 blockade has improved overall survival remarkably in metastatic breast cancer; however, in patients with early stage disease, it has led to small benefits in progression-free survival. Moreover, biologic heterogeneity within HER2-positive disease may determine response to treatment and prognosis. Different subgroups of patients with HER2-positive breast cancer may benefit from different therapeutic approaches. Thus, there is ongoing work to optimize and de-escalate treatment in patients who may do just as well with less therapy and can avoid unnecessary treatments and their related toxicities. The objective of this review is to summarize the background and latest evidence on the current management of early stage, HER2-positive breast cancer and to present novel perspectives on its management.
Topics: Ado-Trastuzumab Emtansine; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Chemotherapy, Adjuvant; Clinical Trials as Topic; Female; Humans; Lapatinib; Maytansine; Progression-Free Survival; Quinolines; Receptor, ErbB-2; Trastuzumab; Treatment Outcome
PubMed: 30291791
DOI: 10.1002/cncr.31657 -
Journal of Nuclear Medicine : Official... Oct 2023The human epidermal growth factor receptor 2 (HER2)-targeting trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) are antibody-drug conjugates (ADC)...
The human epidermal growth factor receptor 2 (HER2)-targeting trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) are antibody-drug conjugates (ADC) clinically used to treat HER2-positive breast cancer, with the latter receiving clinical approval in 2021 for HER2-positive gastric cancer. Lovastatin, a cholesterol-lowering drug, temporally elevates cell-surface HER2 in ways that enhance HER2-ADC binding and internalization. In an NCIN87 gastric xenograft model and a gastric patient-derived xenograft model, we used the Zr-labeled or Cu-labeled anti-HER2 antibody trastuzumab to investigate the dosing regimen of ADC therapy with and without coadministration of lovastatin. We compared the ADC efficacy of a multiple-dose ADC regime, which replicates the clinical dose regimen standard, with a single-dose regime. T-DM1/lovastatin treatment inhibited tumor growth, regardless of multiple- or single-dose T-DM1 administration. Coadministration of lovastatin with T-DM1 or T-DXd as a single dose enhanced tumor growth inhibition, which was accompanied by a decrease in signal on HER2-targeted immuno-PET and a decrease in HER2-mediated signaling at the cellular level. DNA damage signaling was increased on ADC treatment in vitro. Our data from a gastric cancer xenograft show the utility of HER2-targeted immuno-PET to inform the tumor response to ADC therapies in combination with modulators of cell-surface target availability. Our studies also demonstrate that statins enhance ADC efficacy in both a cell-line and a patient-derived xenograft model in ways that enable a single-dose administration of the ADC.
Topics: Humans; Female; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Stomach Neoplasms; Antibodies, Monoclonal, Humanized; Cell Line, Tumor; Trastuzumab; Ado-Trastuzumab Emtansine; Receptor, ErbB-2; Breast Neoplasms; Immunoconjugates; Positron-Emission Tomography; Lovastatin
PubMed: 37385676
DOI: 10.2967/jnumed.122.265172 -
Journal of Biotechnology Jun 2006Because of their ecological functions, natural products have been optimized in evolution for interaction with biological systems and receptors. However, they have not... (Review)
Review
Because of their ecological functions, natural products have been optimized in evolution for interaction with biological systems and receptors. However, they have not necessarily been optimized for other desirable drug properties and thus can often be improved by structural modification. Using examples from the literature, this paper reviews the opportunities for increasing structural diversity among natural products by combinatorial biosynthesis, i.e., the genetic manipulation of biosynthetic pathways. It distinguishes between combinatorial biosynthesis in a narrower sense to generate libraries of modified structures, and metabolic engineering for the targeted formation of specific structural analogs. Some of the problems and limitations encountered with these approaches are also discussed. Work from the author's laboratory on ansamycin antibiotics is presented which illustrates some of the opportunities and limitations.
Topics: Anti-Bacterial Agents; Antineoplastic Agents, Phytogenic; Combinatorial Chemistry Techniques; Drug Design; Genetic Engineering; Maytansine; Molecular Structure; Polyketide Synthases; Rifabutin
PubMed: 16414140
DOI: 10.1016/j.jbiotec.2005.12.001 -
Molecular Cancer Therapeutics Oct 2010Maytansine is a potent microtubule-targeted compound that induces mitotic arrest and kills tumor cells at subnanomolar concentrations. However, its side effects and lack...
Maytansine is a potent microtubule-targeted compound that induces mitotic arrest and kills tumor cells at subnanomolar concentrations. However, its side effects and lack of tumor specificity have prevented successful clinical use. Recently, antibody-conjugated maytansine derivatives have been developed to overcome these drawbacks. Several conjugates show promising early clinical results. We evaluated the effects on microtubule polymerization and dynamic instability of maytansine and two cellular metabolites (S-methyl-DM1 and S-methyl-DM4) of antibody-maytansinoid conjugates that are potent in cells at picomolar levels and that are active in tumor-bearing mice. Although S-methyl-DM1 and S-methyl-DM4 inhibited polymerization more weakly than maytansine, at 100 nmol/L they suppressed dynamic instability more strongly than maytansine (by 84% and 73%, respectively, compared with 45% for maytansine). However, unlike maytansine, S-methyl-DM1 and S-methyl-DM4 induced tubulin aggregates detectable by electron microscopy at concentrations ≥2 μmol/L, with S-methyl-DM4 showing more extensive aggregate formation than S-methyl-DM1. Both maytansine and S-methyl-DM1 bound to tubulin with similar K(D) values (0.86 ± 0.2 and 0.93 ± 0.2 μmol/L, respectively). Tritiated S-methyl-DM1 bound to 37 high-affinity sites per microtubule (K(D), 0.1 ± 0.05 μmol/L). Thus, S-methyl-DM1 binds to high-affinity sites on microtubules 20-fold more strongly than vinblastine. The high-affinity binding is likely at microtubule ends and is responsible for suppression of microtubule dynamic instability. Also, at higher concentrations, S-methyl-DM1 showed low-affinity binding either to a larger number of sites on microtubules or to sedimentable tubulin aggregates. Overall, the maytansine derivatives that result from cellular metabolism of the antibody conjugates are themselves potent microtubule poisons, interacting with microtubules as effectively as or more effectively than the parent molecule.
Topics: Animals; Antineoplastic Agents, Phytogenic; Binding Sites; Cattle; Immunoconjugates; Maytansine; Mice; Microtubules; Polymers; Solubility; Tubulin
PubMed: 20937594
DOI: 10.1158/1535-7163.MCT-10-0644 -
The Journal of Biological Chemistry May 2024Cryptophycins are microtubule-targeting agents (MTAs) that belong to the most potent antimitotic compounds known to date; however, their exact molecular mechanism of...
Cryptophycins are microtubule-targeting agents (MTAs) that belong to the most potent antimitotic compounds known to date; however, their exact molecular mechanism of action remains unclear. Here, we present the 2.2 Å resolution X-ray crystal structure of a potent cryptophycin derivative bound to the αβ-tubulin heterodimer. The structure addresses conformational issues present in a previous 3.3 Å resolution cryo-electron microscopy structure of cryptophycin-52 bound to the maytansine site of β-tubulin. It further provides atomic details on interactions of cryptophycins, which had not been described previously, including ones that are in line with structure-activity relationship studies. Interestingly, we discovered a second cryptophycin-binding site that involves the T5-loop of β-tubulin, a critical secondary structure element involved in the exchange of the guanosine nucleotide and in the formation of longitudinal tubulin contacts in microtubules. Cryptophycins are the first natural ligands found to bind to this new "βT5-loop site" that bridges the maytansine and vinca sites. Our results offer unique avenues to rationally design novel MTAs with the capacity to modulate T5-loop dynamics and to simultaneously engage multiple β-tubulin binding sites.
PubMed: 38735475
DOI: 10.1016/j.jbc.2024.107363 -
Journal of Clinical Oncology : Official... Dec 2016Mesothelin is a tumor antigen that is highly expressed in many human cancers, including malignant mesothelioma and pancreatic, ovarian, and lung adenocarcinomas. It is... (Review)
Review
Mesothelin is a tumor antigen that is highly expressed in many human cancers, including malignant mesothelioma and pancreatic, ovarian, and lung adenocarcinomas. It is an attractive target for cancer immunotherapy because its normal expression is limited to mesothelial cells, which are dispensable. Several antibody-based therapeutic agents as well as vaccine and T-cell therapies directed at mesothelin are undergoing clinical evaluation. These include antimesothelin immunotoxins (SS1P, RG7787/LMB-100), chimeric antimesothelin antibody (amatuximab), mesothelin-directed antibody drug conjugates (anetumab ravtansine, DMOT4039A, BMS-986148), live attenuated Listeria monocytogenes-expressing mesothelin (CRS-207, JNJ-64041757), and chimeric antigen receptor T-cell therapies. Two antimesothelin agents are currently in multicenter clinical registration trials for malignant mesothelioma: amatuximab in the first-line setting and anetumab ravtansine as second-line therapy. Phase II randomized clinical trials of CRS-207 as a boosting agent and in combination with immune checkpoint inhibition for pancreatic cancer are nearing completion. These ongoing studies will define the utility of mesothelin immunotherapy for treating cancer.
Topics: Animals; Antibodies, Monoclonal; Antigens, Neoplasm; Antineoplastic Agents; Clinical Trials as Topic; GPI-Linked Proteins; Humans; Immunoconjugates; Immunotherapy; Maytansine; Mesothelin; Neoplasms
PubMed: 27863199
DOI: 10.1200/JCO.2016.68.3672 -
The Oncologist Oct 2023Antibody-drug conjugates (ADCs) have been the preferred regimens for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) after...
BACKGROUND
Antibody-drug conjugates (ADCs) have been the preferred regimens for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) after trastuzumab. Unfortunately, there is little data showing which ADCs should be chosen for those patients whose treatment with tyrosine kinase inhibitors (TKIs) failed. This study aims to analyze the efficacy and safety between novel anti-HER2 ADCs and trastuzumab emtansine (T-DM1) for those with TKIs failure.
MATERIALS AND METHODS
HER2-positive MBC using ADCs from January 2013 to June 2022 were included, and all of them were treated with TKIs. The primary study endpoint was progression-free survival (PFS), and the secondary study endpoints were objective response rate (ORR), clinical benefit rate (CBR), and safety.
RESULTS
A total of 144 patients with 73 patients in the novel anti-HER2 ADCs group and 71 patients in the T-DM1 group. In these novel ADCs, 30 patients received trastuzumab deruxtecan (T-Dxd), 43 patients receive other novel ADCs. The median PFS in the novel ADCs group and T-DM1 group were 7.0 months versus 4.0 months, respectively, and ORR was 54.8% versus 22.5%, CBR was 65.8% versus 47.9%, respectively. In subgroups analysis, the PFS were both significantly improved in patients receiving T-Dxd and other novel ADCs compared with T-DM1. The most common grades 3-4 adverse events in the novel anti-HER-2 ADCs group were neutropenia (20.5%) and thrombocytopenia (28.1%) in the T-DM1 group.
CONCLUSIONS
In patients with HER2-positive MBC previously treated with TKIs, both T-Dxd and other novel anti-HER2 ADCs yielded statistically significant better PFS than T-DM1 did, with tolerable toxicities.
Topics: Female; Humans; Ado-Trastuzumab Emtansine; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Immunoconjugates; Receptor, ErbB-2; Trastuzumab; Tyrosine Kinase Inhibitors
PubMed: 37218076
DOI: 10.1093/oncolo/oyad127 -
Gynecologic Oncology Oct 2018To evaluate the safety profile and preliminary antitumor activity of mirvetuximab soravtansine when administered in combination with carboplatin to relapsed ovarian...
Safety and activity findings from a phase 1b escalation study of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with carboplatin in patients with platinum-sensitive ovarian cancer.
PURPOSE
To evaluate the safety profile and preliminary antitumor activity of mirvetuximab soravtansine when administered in combination with carboplatin to relapsed ovarian cancer patients.
METHODS
Patients with recurrent, platinum-sensitive epithelial ovarian or fallopian tube cancer were enrolled. Eligibility included a minimum requirement of tumor FRα positivity (≥25% of cells with ≥2+ staining intensity). Patients received escalating doses of mirvetuximab soravtansine and carboplatin on day 1 of a 21-day cycle (once every 3 weeks). Mirvetuximab soravtansine maintenance therapy was permitted, at the investigators discretion, following cessation of carboplatin treatment. Adverse events, tumor response, and progression-free survival (PFS) were determined.
RESULTS
Eighteen patients were enrolled and dosed with combination therapy; thirteen continued with mirvetuximab soravtansine maintenance following carboplatin discontinuation. Mirvetuximab soravtansine dosing was escalated from 5 to 6 mg/kg (adjusted ideal body weight) and carboplatin from AUC4 to AUC5. Adverse events were generally mild (≤ grade 2) with nausea, diarrhea, thrombocytopenia, blurred vision, and fatigue being the most common treatment-emergent toxicities. For all evaluable patients (n = 17), the confirmed objective response rate (ORR) was 71%, including three complete responses and nine partial responses, and the median PFS was 15 months. A median duration of response was not reached.
CONCLUSION
These data demonstrate that mirvetuximab soravtansine combined with carboplatin is a well-tolerated and highly active regimen in recurrent, platinum-sensitive ovarian cancer. Further evaluation of this combination in a randomized fashion is warranted.
Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cohort Studies; Diarrhea; Disease-Free Survival; Drug Resistance, Neoplasm; Fallopian Tube Neoplasms; Fatigue; Female; Folate Receptor 1; Humans; Immunoconjugates; Incidence; Maximum Tolerated Dose; Maytansine; Middle Aged; Nausea; Neoplasm Recurrence, Local; Ovarian Neoplasms; Thrombocytopenia; Treatment Outcome
PubMed: 30093227
DOI: 10.1016/j.ygyno.2018.07.017 -
International Journal of Molecular... May 2023Despite the great progress made in the understanding of the biological behavior of certain types of invasive breast cancer, there is still no single histological or... (Review)
Review
Despite the great progress made in the understanding of the biological behavior of certain types of invasive breast cancer, there is still no single histological or molecular classification that encompasses such diversity and accurately predicts the clinical course of distinct breast cancer subtypes. The long-lasting classification of breast cancer as HER2-positive vs. HER2-negative has recently come into question with the discovery of new antibody drug conjugates (ADC), which are proven to be remarkably efficient in treating HER2-low breast cancer. The HER2-low paradigm has challenged the traditional understanding of HER2 overexpression and emphasized the need for more robust HER2 testing in order to encompass HER2 intratumoral heterogeneity and spatial distribution more accurately. It is yet to be seen if low HER2 will remain merely a marker of HER2-equipped tumors targetable with ADCs or if distinctive molecular and phenotypic groups within HER2-low tumors will eventually be discerned.
Topics: Humans; Female; Trastuzumab; Breast Neoplasms; Ado-Trastuzumab Emtansine; Receptor, ErbB-2; Antineoplastic Agents; Immunoconjugates; Camptothecin
PubMed: 37175916
DOI: 10.3390/ijms24098206