Mirvetuximab soravtansine: A breakthrough in targeted therapy for platinum-resistant ovarian cancer.

Ovarian cancer, ranked as the second leading cause of gynecologic malignancy-related deaths globally, poses a formidable challenge despite advances in early detection and treatment modalities. This paper explores the efficacy and safety of mirvetuximab soravtansine, the first folate receptor alpha (FRα)-targeting antibody-drug conjugate, in platinum-resistant ovarian cancer expressing FRα. A review of 4 key studies involving 453 participants consistently demonstrates mirvetuximab soravtansine's clinically meaningful antitumor activity and favorable safety profile. Clinical implications emphasize mirvetuximab soravtansine's pivotal role in targeted therapy, especially for high FRα-expressing tumors, potentially reshaping platinum-resistant ovarian cancer management. The combination therapy approach introduces a novel dimension, suggesting enhanced therapeutic outcomes. Even in heavily pretreated patients, mirvetuximab soravtansine's favorable tolerability positions it as a viable option. The reliability of archival tissue for FRα assessment simplifies patient selection, streamlining accessibility to targeted therapies. However, identified gaps, including limited diversity in patient populations, sparse quality of life data, and the need for long-term safety information, indicate areas for future research. Exploration of additional biomarkers predicting mirvetuximab soravtansine responsiveness is essential for personalized treatment.

CyTOF analysis revealed platelet heterogeneity in breast cancer patients received T-DM1 treatment.

T-DM1 (Trastuzumab Emtansine) belongs to class of Antibody-Drug Conjugates (ADC), where cytotoxic drugs are conjugated with the antibody Trastuzumab to specifically target HER2-positive cancer cells. Platelets, as vital components of the blood system, intricately influence the immune response to tumors through complex mechanisms. In our study, we examined platelet surface proteins in the plasma of patients before and after T-DM1 treatment, categorizing them based on treatment response. We identified a subgroup of platelets with elevated expression of CD63 and CD9 exclusively in patients with favorable treatment responses, while this subgroup was absent in patients with poor responses. Another noteworthy discovery was the elevated expression of CD36 in the platelet subgroups of patients exhibiting inadequate responses to treatment. These findings suggest that the expression of these platelet surface proteins may be correlated with the prognosis of T-DM1 treatment. These indicators offer valuable insights for predicting the therapeutic response to T-DM1 and may become important references in future clinical practice, contributing to a better understanding of the impact of ADC therapies and optimizing personalized cancer treatment strategies.

Quantifying payloads of antibody‒drug conjugates using a postcolumn infused-internal standard strategy with LC‒MS.

BACKGROUND: Antibody‒drug conjugates (ADCs) are innovative biopharmaceutics consisting of a monoclonal antibody, linkers, and cytotoxic payloads. Monitoring circulating payload concentrations has the potential to identify ADC toxicity; however, accurate quantification faces challenges, including low plasma concentrations, severe matrix effects, and the absence of stable isotope-labeled internal standards (SIL-IS) for payloads and their derivatives. Previous studies used structural analogs as internal standards, but different retention times between structural analogs and target analytes may hinder effective matrix correction. Therefore, a more flexible approach is required for precise payload quantification. RESULTS: We developed an LC‒MS/MS method incorporating a postcolumn-infused internal standard (PCI-IS) strategy for quantifying payloads and their derivatives of trastuzumab emtansine, trastuzumab deruxtecan, and sacituzumab govitecan, including DM1, MCC-DM1, DXd, SN-38, and SN-38G. Structural analogs (maytansine, Lys-MCC-DM1, and exatecan) were selected as PCI-IS candidates, and their accuracy performance was evaluated based on the percentage of samples within 80%-120% quantification accuracy. Compared to the approach without PCI-IS correction, exatecan enhanced the accuracy performance from 30-40%-100% for SN-38 and DXd, while maytansine and Lys-MCC-DM1 showed comparable accuracy for DM1 and MCC-DM1. This validated PCI-IS analytical method showed superior normalization of matrix effect in all analytes compared to the conventional internal standard approach. The clinical application of this approach showed pronounced differences in DXd and SN-38 concentrations before and after PCI-IS correction. Moreover, only DXd concentrations after PCI-IS correction were significantly higher in patients with thrombocytopenia (p = 0.037). SIGNIFICANCE: This approach effectively addressed the issue of unavailability of SIL-IS for novel ADC payloads and provided more accurate quantification, potentially yielding more robust statistical outcomes for understanding the exposure-toxicity relationship in ADCs. It is anticipated that this PCI-IS strategy may be extrapolated to quantify payloads and derivatives in diverse ADCs, thereby providing invaluable insights into drug toxicity and fortifying patient safety in ADC usage.

Effects of trastuzumab emtansine on canine urothelial carcinoma cells in vitro and in vivo.

Urothelial carcinoma (UC) is the most common malignancy of the urinary tract in dogs and has aggressive behaviour. Although human epidermal growth factor receptor 2 (HER2) is a known therapeutic target with evidence in canine UC, the efficacy of anti-HER2 antibody drugs remains unknown. This study aimed to investigate the effects of anti-HER2 antibody drugs including trastuzumab and trastuzumab emtansine (T-DM1) on canine UC cell lines in vitro and in vivo. Four canine UC cell lines (Nene, TCCUB, Love, and Sora) were used. In western blotting, HER2 protein expression was observed in all the cell lines. Although both trastuzumab and T-DM1 showed dose-dependent growth inhibitory activity in the cell lines, T-DM1 showed much stronger activity than that of trastuzumab. In flow cytometry analyses with the canine UC cell line (Sora), T-DM1 but not trastuzumab significantly increased the percentages of early and late apoptotic cells in annexin V apoptotic assays and the sub-G1 phase fraction in cell cycle analyses. For the in vivo experiment, the canine UC cells (Sora) were subcutaneously injected into nude mice. Four days after inoculation, trastuzumab, T-DM1, or vehicle was administered intraperitoneally once a week for three times. Tumour volumes were significantly smaller in the T-DM1 group compared to the trastuzumab and vehicle control groups. These findings indicate that T-DM1 exerts a stronger antitumour effect than that of trastuzumab on canine UC cells in vitro and in vivo, possibly by inducing apoptosis due to DM1.

Population-level impact of adjuvant trastuzumab emtansine on the incidence of metastatic breast cancer: an epidemiological prediction model of women with HER2-positive early breast cancer and residual disease following neoadjuvant therapy.

PURPOSE: Treating early-stage breast cancer (eBC) may delay or prevent subsequent metastatic breast cancer (mBC). In the phase 3 KATHERINE study, women with human epidermal growth factor receptor 2 (HER2)-positive eBC with residual disease following neoadjuvant therapy containing trastuzumab and a taxane experienced 50% reductions in disease recurrence or death when treated with adjuvant trastuzumab emtansine (T-DM1) vs adjuvant trastuzumab. We predicted the population-level impact of adjuvant T-DM1 on mBC occurrence in five European countries (EU5) and Canada from 2021-2030. METHODS: An epidemiological prediction model using data from national cancer registries, observational studies, and clinical trials was developed. Assuming 80% population-level uptake of adjuvant treatment, KATHERINE data were extrapolated prospectively to model projections. Robustness was evaluated in alternative scenarios. RESULTS: We projected an eligible population of 116,335 women in Canada and the EU5 who may be diagnosed with HER2-positive eBC and have residual disease following neoadjuvant therapy from 2021-2030. In EU5, the cumulative number of women projected to experience relapsed mBC over the 10-year study period was 36,009 vs 27,143 under adjuvant trastuzumab vs T-DM1, a difference of 8,866 women, equivalent to 25% fewer cases with the use of adjuvant T-DM1 in EU5 countries from 2021-2030. Findings were similar for Canada. CONCLUSION: Our models predicted greater reductions in the occurrence of relapsed mBC with adjuvant T-DM1 vs trastuzumab in the indicated populations in EU5 and Canada. Introduction of T-DM1 has the potential to reduce population-level disease burden of HER2-positive mBC in the geographies studied.

Mirvetuximab Soravtansine in FRα-Positive, Platinum-Resistant Ovarian Cancer.

BACKGROUND: Mirvetuximab soravtansine-gynx (MIRV), a first-in-class antibody-drug conjugate targeting folate receptor α (FRα), is approved for the treatment of platinum-resistant ovarian cancer in the United States. METHODS: We conducted a phase 3, global, confirmatory, open-label, randomized, controlled trial to compare the efficacy and safety of MIRV with the investigator's choice of chemotherapy in the treatment of platinum-resistant, high-grade serous ovarian cancer. Participants who had previously received one to three lines of therapy and had high FRα tumor expression (≥75% of cells with ≥2+ staining intensity) were randomly assigned in a 1:1 ratio to receive MIRV (6 mg per kilogram of adjusted ideal body weight every 3 weeks) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary end point was investigator-assessed progression-free survival; key secondary analytic end points included objective response, overall survival, and participant-reported outcomes. RESULTS: A total of 453 participants underwent randomization; 227 were assigned to the MIRV group and 226 to the chemotherapy group. The median progression-free survival was 5.62 months (95% confidence interval [CI], 4.34 to 5.95) with MIRV and 3.98 months (95% CI, 2.86 to 4.47) with chemotherapy (P<0.001). An objective response occurred in 42.3% of the participants in the MIRV group and in 15.9% of those in the chemotherapy group (odds ratio, 3.81; 95% CI, 2.44 to 5.94; P<0.001). Overall survival was significantly longer with MIRV than with chemotherapy (median, 16.46 months vs. 12.75 months; hazard ratio for death, 0.67; 95% CI, 0.50 to 0.89; P = 0.005). During the treatment period, fewer adverse events of grade 3 or higher occurred with MIRV than with chemotherapy (41.7% vs. 54.1%), as did serious adverse events of any grade (23.9% vs. 32.9%) and events leading to discontinuation (9.2% vs. 15.9%). CONCLUSIONS: Among participants with platinum-resistant, FRα-positive ovarian cancer, treatment with MIRV showed a significant benefit over chemotherapy with respect to progression-free and overall survival and objective response. (Funded by ImmunoGen; MIRASOL ClinicalTrials.gov number, NCT04209855.).

Real world data on the demographic and clinicopathological profile and management of patients with early-stage HER2-positive breast cancer and residual disease treated with adjuvant trastuzumab emtansine (KARMA study).

INTRODUCTION: Trastuzumab emtansine (T-DM1) significantly improves invasive disease-free survival and reduces the risk of recurrence in patients with HER2-positive early breast cancer (EBC) with residual disease (RD). The KARMA study aimed to describe the characteristics and management of these patients in clinical practice in Spain. MATERIAL AND METHODS: We conducted a multicentre retrospective study in patients with HER2-positive EBC with RD following neoadjuvant treatment (NeoT) and who had received ≥1 dose of T-DM1 as adjuvant treatment. The primary endpoint was the evaluation of sociodemographic and clinicopathological characteristics of these patients. RESULTS: A total of 114 patients were included (March-July 2020). At diagnosis, most tumours were infiltrating ductal carcinoma (IDC) (93.9 %), grade 2 (56.1 %), and hormone receptor (HR)-positive (79.8 %). Over 75 % of patients had disease in operable clinical stages (T1-3 N0-1). In the neoadjuvant setting, 86.8 % of patients received trastuzumab plus pertuzumab, and 23.6 % achieved radiological complete response. Breast-conserving surgery was performed in 55.8 % of patients. Surgical specimens showed that 89.5 % of patients had IDC, 49.1 % grade 2, 84.1 % HR-positive, and 8.3 % HER2-negative disease. Most patients had RD classified as RCB-II and Miller/Payne grade 3/4. Grade 3 treatment-related adverse events (trAEs) occurred in 5.3 % of patients. No grade 4/5 AEs occurred. Over 95 % of patients were free of invasive-disease during T-DM1 adjuvant treatment. CONCLUSION: The KARMA study describes the characteristics of patients with HER2-positive EBC with RD after NeoT and the real-life management of a T-DM1 adjuvant regimen, which showed a manageable safety profile in line with the KATHERINE trial data.

Cost-utility analysis of trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer in Chinese setting.

PURPOSE: Trastuzumab deruxtecan (T-DXd) expressed substantial improvement in the progression-free survival and overall survival contrasted with trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer (mBC), becoming the second-line standard of care, promisingly. We aim to estimate the cost-utility of T-DXd versus T-DM1 in HER2-positive mBC from the Chinese healthcare perspective. METHODS: A partitioned survival model was applied to examine the cost-utility of T-DXd versus T-DM1. Clinical patients and outcome data were sourced from the DESTINY-Breast 03 trial. Costs and utilities were sourced in Chinese setting. Total costs, quality-adjusted life months (QALMs), and an incremental cost-utility ratios (ICUR) were calculated for cost-utility analysis. The willingness-to-pay threshold was set at $3188/QALM. Univariate, scenario, and probabilistic sensitivity analyses were performed. RESULTS: T-DXd group gained ∆QALM of 7.09 months and ∆Cost of $304,503 compared with T-DM1 therapy, which caused an ICUR of $42,936/QALM. The results of sensitivity analyses confirmed the base-case findings. Furthermore, T-DXd must reduce the price to enter the Chinese mainland market. At least when the cycle cost of T-DXd is reduced to $2975, T-DXd has an 83.3% chance of becoming a better choice. CONCLUSIONS: T-DXd appears to be not cost effective compared with T-DM1 for HER2-positive mBC patients previously treated with trastuzumab and a taxane.

Macrolide and Ketolide Antibiotics Inhibit the Cytotoxic Effect of Trastuzumab Emtansine in HER2-Positive Breast Cancer Cells: Implication of a Potential Drug-ADC Interaction in Cancer Chemotherapy.

Macrolides are widely used for the long-term treatment of infections and chronic inflammatory diseases. The pharmacokinetic features of macrolides include extensive tissue distribution because of favorable membrane permeability and accumulation within lysosomes. Trastuzumab emtansine (T-DM1), a HER2-targeting antibody-drug conjugate (ADC), is catabolized in the lysosomes, where Lys-SMCC-DM1, a potent cytotoxic agent, is processed by proteinase degradation and subsequently released from the lysosomes to the cytoplasm through the lysosomal membrane transporter SLC46A3, resulting in an antitumor effect. We recently demonstrated that erythromycin and clarithromycin inhibit SLC46A3 and attenuate the cytotoxicity of T-DM1; however, the effect of other macrolides and ketolides has not been determined. In this study, we evaluated the effect of macrolide and ketolide antibiotics on T-DM1 cytotoxicity in a human breast cancer cell line, KPL-4. Macrolides used in the clinic, such as roxithromycin, azithromycin, and josamycin, as well as solithromycin, a ketolide under clinical development, significantly attenuated T-DM1 cytotoxicity in addition to erythromycin and clarithromycin. Of these, azithromycin was the most potent inhibitor of T-DM1 efficacy. These antibiotics significantly inhibited the transport function of SLC46A3 in a concentration-dependent manner. Moreover, these compounds extensively accumulated in the lysosomes at the levels estimated to be 0.41-13.6 mM when cells were incubated with them at a 2 µM concentration. The immunofluorescence staining of trastuzumab revealed that azithromycin and solithromycin inhibit the degradation of T-DM1 in the lysosomes. These results suggest that the attenuation of T-DM1 cytotoxicity by macrolide and ketolide antibiotics involves their lysosomal accumulation and results in their greater lysosomal concentrations to inhibit the SLC46A3 function and T-DM1 degradation. This suggests a potential drug-ADC interaction during cancer chemotherapy.

New insights into the anticancer therapeutic potential of maytansine and its derivatives.

Maytansine is a pharmacologically active 19-membered ansamacrolide derived from various medicinal plants and microorganisms. Among the most studied pharmacological activities of maytansine over the past few decades are anticancer and anti-bacterial effects. The anticancer mechanism of action is primarily mediated through interaction with the tubulin thereby inhibiting the assembly of microtubules. This ultimately leads to decreased stability of microtubule dynamics and cause cell cycle arrest, resulting in apoptosis. Despite its potent pharmacological effects, the therapeutic applications of maytansine in clinical medicine are quite limited due to its non-selective cytotoxicity. To overcome these limitations, several derivatives have been designed and developed mostly by modifying the parent structural skeleton of maytansine. These structural derivatives exhibit improved pharmacological activities as compared to maytansine. The present review provides a valuable insight into maytansine and its synthetic derivatives as anticancer agents.

Do statins enhance the antitumor effect of trastuzumab emtansine (T-DM1)?: Real-life cohort.

Human epidermal growth factor receptor 2 (HER2)-targeting therapies have become crucial in the management of HER2-positive breast cancer. Trastuzumab emtansine (T-DM1) is a microtubule inhibitor and HER2-targeted antibody conjugate. T-DM1 resistance is most likely influenced by factors involved in the biological mechanisms of T-DM1 action. This study aimed to examine the efficacy of statins, which influence HER-2-based therapies via the caveolin-1 (CAV-1) protein, in female breast cancer patients receiving T-DM1. Our study included 105 patients with HER2-positive metastatic breast cancer treated with T-DM1. The progression-free survival (PFS) and overall survival (OS) of patients who received statins concurrently with T-DM1 versus those who did not were compared. During the median 39.5 (95% confidence interval [CI]: 35.6-43.5) months of follow-up, 16 (15.2%) patients received statins, and 89 (84.8%) patients did not. Median OS was significantly higher in patients using statins than in patients not using statins (58.8 vs 26.5 months, P = .016). The association between statin use and PFS did not reach statistical significance (34.7 vs 9.9 months, P = .159). Multivariate Cox regression analysis showed that better performance status (hormone receptor [HR]: 0.30, 95% CI: 0.13-0.71, P = .006), use of trastuzumab plus pertuzumab prior to T-DM1 (HR: 0.37, 95% CI: 0.18-0.76, P = .007) and use of statins with T-DM1 (HR: 0.29, 95% CI: 0.12-0.70, P = .006) were independent factors that prolong OS duration. Our study showed that T-DM1 is more effective at treating HER2-positive breast cancer in people who receive statins concurrently with T-DM1 than those who do not.

Trastuzumab emtansine vs lapatinib and capecitabine in HER2-positive metastatic breast cancer brain metastases: A real-world study.

BACKGROUND: Trastuzumab emtansine (T-DM1) has demonstrated improvements in survival and neurological symptoms in patients with breast cancer with brain metastases (BCBM). This real-world study investigated the effectiveness of T-DM1 versus lapatinib plus capecitabine (LC) in patients with BCBM. METHODS: This retrospective, observational study evaluated patients with HER2-positive BCBM using a real-world database. Eligible patients had initiated T-DM1 or LC with a prior diagnosis of brain metastasis and ≥1 prior metastatic breast cancer treatment. The primary endpoint was overall survival (OS); secondary endpoints were time to next relevant treatment or death (TTNT) and real-world progression-free survival (rwPFS). An inverse probability of treatment weighting (IPTW) approach was used to account for differences in potential baseline characteristics between treatment groups. Outcomes were described using the Kaplan-Meier method, and the average treatment effect of initiating T-DM1 versus LC was estimated using weighted Cox proportional hazard models and hazard ratio (HR). RESULTS: A total of 214 patients were available for analysis (T-DM1, n = 161; LC, n = 53). Demographics and baseline characteristics were generally well-balanced between treatment groups after weighting. After weighting, median OS was 17.7 (T-DM1) versus 9.6 (LC) months (HR, 0.55 [95% CI, 0.34-0.89]; P=0.013). Median TTNT was 9.0 (T-DM1) versus 6.0 (LC) months (HR, 0.55 [95% CI, 0.36-0.85]; P = 0.005). After weighting, median rwPFS was 6.0 (T-DM1) versus 4.0 (LC) months (HR, 0.50 [95% CI, 0.36-0.69]; P < 0.001). CONCLUSIONS: These results support the superior effectiveness and clinical relevance of T-DM1 versus LC in patients with HER2-positive BCBM in the real world.

Disease-driven engineering of peptide-targeted DM1 loaded liposomal nanoparticles for enhanced efficacy in treating multiple myeloma by exploring DM1 prodrug chemistry.

Here, we report a CD138 receptor targeting liposomal formulation (TNP[Prodrug-4]) that achieved efficacious tumor growth inhibition in treating multiple myeloma by overcoming the dose limiting severe toxicity issues of a highly potent drug, Mertansine (DM1). Despite the promising potential to treat various cancers, due to poor solubility and pharmacokinetic profile, DM1's translation to the clinic has been unsatisfactory. We hypothesized that the optimal prodrug chemistry would promote efficient loading of the prodrug into targeted nanoparticles and achieve controlled release following endocytosis by the cancer cells, consequently, accomplish the most potent tumor growth inhibition. We evaluated four functional linker chemistries for synthesizing DM1-Prodrug molecules and evaluated their stability and cancer cell toxicity in vitro. It was determined that the phosphodiester moiety, as part of nanoparticle formulations, demonstrated most favorable characteristics with an IC50 of ∼16 nM. Nanoparticle formulations of Prodrug-4 enabled its administration at 8-fold higher dosage of equivalent free drug while remaining below maximum tolerated dose. Importantly, TNP[Prodrug-4] achieved near complete inhibition of tumor growth (∼99% by day 10) compared to control, without displaying noticeable systemic toxicity. TNP[Prodrug-4] promises a formulation that could potentially make DM1 treatment available for wider clinical applications with a long-term goal for better patient outcomes.

HER2DX ERBB2 mRNA expression in advanced HER2-positive breast cancer treated with T-DM1.

In advanced HER2-positive (HER2+) breast cancer, the new antibody-drug conjugate trastuzumab deruxtecan is more effective compared with trastuzumab emtansine (T-DM1). However, trastuzumab deruxtecan can have considerable toxicities, and the right treatment sequence is unknown. Biomarkers to guide the use of anti-HER2 therapies beyond HER2 status are needed. Here, we evaluated if preestablished levels of ERBB2 mRNA expression according to the HER2DX standardized assay are associated with response and survival following T-DM1. In ERBB2 low, medium, and high groups, the overall response rate was 0%, 29%, and 56%, respectively (P < .001). ERBB2 mRNA was statistically significantly associated with better progression-free survival (P = .002) and overall survival (OS; P = .02). These findings were independent of HER2 immunohistochemistry (IHC) levels, hormone receptor, age, brain metastasis, and line of therapy. The HER2DX risk score (P = .04) and immunoglobulin signature (P = .04) were statistically significantly associated with overall survival since diagnosis. HER2DX provides prognostic and predictive information following T-DM1 in advanced HER2+ breast cancer.

Antibody-Drug Conjugates for the Treatment of HER2-Positive Breast Cancer.

Human epidermal growth factor receptor 2 (HER2) receptor tyrosine kinase is overexpressed in 20-30% of breast cancers and is associated with poor prognosis and worse overall patient survival. Most women with HER2-positive breast cancer receive neoadjuvant chemotherapy plus HER2-targeted therapies. The development of HER2-directed therapeutics is an important advancement in targeting invasive breast cancer. Despite the efficacy of anti-HER2 monoclonal antibodies, they are still being combined with adjuvant chemotherapy to improve overall patient outcomes. Recently, significant progress has been made towards the development of a class of therapeutics known as antibody-drug conjugates (ADCs), which leverage the high specificity of HER2-targeted monoclonal antibodies with the potent cytotoxic effects of various small molecules, such as tubulin inhibitors and topoisomerase inhibitors. To date, two HER2-targeting ADCs have been approved by the FDA for the treatment of HER2-positive breast cancer: Ado-trastuzumab emtansine (T-DM1; Kadcyla®) and fam-trastuzumab deruxtecan-nxki (T-Dxd; Enhertu®). Kadcyla and Enhertu are approved for use as a second-line treatment after trastuzumab-taxane-based therapy in patients with HER2-positive breast cancer. The success of ADCs in the treatment of HER2-positive breast cancer provides novel therapeutic advancements in the management of the disease. In this review, we discuss the basic biology of HER2, its downstream signaling pathways, currently available anti-HER2 therapeutic modalities and their mechanisms of action, and the latest clinical and safety characteristics of ADCs used for the treatment of HER2-positive breast cancer.

The Dawn of the Antibody-Drug Conjugates Era: How T-DM1 Reinvented the Future of Chemotherapy for Solid Tumors.

Delivering targeted chemotherapy through antibody-drug conjugates (ADC) has emerged as an extremely effective therapeutic strategy for multiple types of cancer. The first agent of this class to be established for treating a solid tumor was trastuzumab emtansine (T-DM1), approved in 2013 for the treatment of HER2-positive metastatic breast cancer. Much of the knowledge that led to this approval came from the landmark Cancer Research publication by Lewis Phillips and colleagues in 2008, where they described the in vitro and in vivo efficacy, pharmacokinetics, and toxicity of T-DM1, demonstrating its relevant preclinical activity against HER2-positive breast cancer models. In this article, the authors also explored the use of different linkers to conjugate the cytotoxic payload to the trastuzumab vehicle, demonstrating improved stability, efficacy, and tolerability of the compound when adopting a specific thioether linker. The findings from this work not only set the stage for the clinical development of T-DM1, but also highlighted the modularity of ADCs, with small changes in their components able to dramatically impact their activity and toxicity. This finding would prove key for the development of novel ADCs, several of which are now reshaping the way we treat breast cancer and other cancer types. In this commentary, we discuss the key implications of the work by Phillips and colleagues, putting it in context of the current and anticipated expansion in the use of ADCs to treat cancer. See related article by Phillips et al., Cancer Res 2008;68:9280-90.

A Novel Antibody-Drug Conjugate Targeting Nectin-2 Suppresses Ovarian Cancer Progression in Mouse Xenograft Models.

Ovarian cancer is the fifth leading cause of cancer, followed by front line is mostly platinum agents and PARP inhibitors, and very limited option in later lines. Therefore, there is a need for alternative therapeutic options. Nectin-2, which is overexpressed in ovarian cancer, is a known immune checkpoint that deregulates immune cell function. In this study, we generated a novel anti-nectin-2 antibody (chimeric 12G1, c12G1), and further characterized it using epitope mapping, enzyme-linked immunosorbent assay, surface plasmon resonance, fluorescence-activated cell sorting, and internalization assays. The c12G1 antibody specifically bound to the C2 domain of human nectin-2 with high affinity (KD = 2.90 × 10-10 M), but not to mouse nectin-2. We then generated an antibody-drug conjugate comprising the c12G1 antibody conjugated to DM1 and investigated its cytotoxic effects against cancer cells in vitro and in vivo. c12G1-DM1 induced cell cycle arrest at the mitotic phase in nectin-2-positive ovarian cancer cells, but not in nectin-2-negative cancer cells. c12G1-DM1 induced ~100-fold cytotoxicity in ovarian cancer cells, with an IC50 in the range of 0.1 nM~7.4 nM, compared to normal IgG-DM1. In addition, c12G1-DM1 showed ~91% tumor growth inhibition in mouse xenograft models transplanted with OV-90 cells. These results suggest that c12G1-DM1 could be used as a potential therapeutic agent against nectin-2-positive ovarian cancers.