Antibody-drug Conjugate Therapy Research Articles

Research Progress of Antibody-Drug Conjugate Therapy for Advanced Gastric Cancer.

Gastric cancer is an intractable malignant tumor that has the fifth highest morbidity and the third highest mortality in the world. Even though various treatment options did much to ameliorate the prognosis of advanced gastric cancer, the survival time remained unsatisfactory. It is significant to develop new therapeutic agents to improve the long-term outcome. Antibody–drug conjugate is an innovative and potent antineoplastic drug composed of a specifically targeted monoclonal antibody, a chemical linker, and a small molecule cytotoxic payload. Powerful therapeutic efficacy and moderate toxicity are its preponderant advantages, which imply the inevitable pharmaceutical developments to meet the demand for individualized precision therapy. Nevertheless, it is unavoidable that there is a phenomenon of drug resistance in this agent. This article systematically reviewed the recent progress of antibody–drug conjugates in advanced gastric cancer therapy.

89Zr]ZrDFO-CR011 PET Correlates with Response to Glycoprotein Nonmetastatic Melanoma B-targeted Therapy in Triple-negative Breast Cancer.

There is a need for prognostic markers to select patients most likely to benefit from antibody-drug conjugate (ADC) therapy. We quantified the relationship between pretreatment PET imaging of glycoprotein nonmetastatic melanoma B (gpNMB) with 89Zr-labeled anti-gpNMB antibody ([89Zr]ZrDFO-CR011) and response to ADC therapy (CDX-011) in triple-negative breast cancer. First, we compared different PET imaging metrics and found that standardized uptake values (SUV) and tumor-to-heart SUV ratios were sufficient to delineate differences in radiotracer uptake in the tumor of four different cell- and patient-derived tumor models and achieved high standardized effect sizes. These tumor models with varying levels of gpNMB expression were imaged with [89Zr]ZrDFO-CR011 followed by treatment with a single bolus injection of CDX-011. The percent change in tumor volume relative to baseline (% CTV) was then correlated with SUVmean of [89Zr]ZrDFO-CR011 uptake in the tumor. All gpNMB-positive tumor models responded to CDX-011 over 6 weeks of treatment, except one patient-derived tumor regrew after 4 weeks of treatment. As expected, the gpNMB-negative tumor increased in volume by 130 ± 59% at endpoint. The magnitude of pretreatment SUV had the strongest inverse correlation with the % CTV at 2-4 weeks after treatment with CDX-011 (Spearman ρ = -0.8). However, pretreatment PET imaging with [89Zr]ZrDFO-CR011 did not inform on which tumor types will regrow over time. Other methods will be needed to predict resistance to treatment.

TROPiCS-04: Study of sacituzumab govitecan (SG) in patients (pts) with locally advanced (LA) unresectable or metastatic urothelial cancer (mUC) that has progressed after prior platinum (PLT) and checkpoint inhibitor (CPI) therapy.

TPS582 Background: Treatment options are limited for pts with LA unresectable or mUC who progress after prior PLT-based and CPI therapies. SG is an antibody-drug conjugate (ADC) composed of an anti-trophopblast cell surface antigen 2 (Trop-2) antibody coupled to SN-38 (a topoisomerase-I inhibitor) via a proprietary hydrolyzable linker. In the phase 2 registrational study TROPHY-U-01 (NCT03547973), SG demonstrated an objective response rate (ORR) of 27% and median overall survival (OS) of 10.9 months in pts with mUC who progressed after prior PLT-based and CPI therapies (n = 113; median, 3 prior lines of therapy; 84% with ≥1 Bellmunt risk factors; Tagawa et al, J Clin Oncol. 2021). These results compared favorably with historic data for single-agent chemotherapy (ORR, ̃18%; OS, 9 months; Powles et al. J Clin Oncol. 2021) and led to accelerated approval of SG by the US Food and Drug Administration for pts with LA or mUC who previously received a PLT-containing chemotherapy and CPI. The phase 3 TROPiCS-04 trial has been initiated to confirm these findings. Methods: TROPiCS-04 (NCT04527991) is a global, multicenter, open-label, randomized, controlled trial in pts with LA unresectable or mUC who progressed after prior PLT-based and CPI therapies. Key eligibility requirements include Eastern Cooperative Oncology Group performance status 0-1; no prior CPI or ADC therapy within 4 weeks of study drug initiation; no history of active interstitial lung disease or noninfectious pneumonitis; and adequate hematologic, hepatic, and renal function. Pts will be randomly assigned 1:1 to receive SG 10 mg/kg intravenously (IV) on days 1 and 8 of 21-day cycles or single-agent treatment of physician’s choice (paclitaxel 175 mg/m2, docetaxel 75 mg/m2, or vinflunine 320 mg/m2 IV on day 1 of 21-day cycles) until progressive disease, unacceptable toxicity, or withdrawal of consent. Treatment beyond progressive disease may be permitted in pts deemed to be receiving clinical benefit per investigator assessment. Approximately 600 pts will be enrolled across ̃280 sites in 3 regions (North America, Europe, and Asia-Pacific) to provide 90% power on the primary endpoint of OS. Secondary endpoints include progression-free survival, ORR, clinical benefit rate, duration of response (all per Response Evaluation Criteria in Solid Tumors version 1.1 by blinded independent central review and investigator assessment), safety, and quality of life. Study enrollment started in January 2021 and is ongoing with pts currently enrolled at 30 sites across all 3 regions. Clinical trial information: NCT04527991.

TROPHY-U-01 cohort 4: Sacituzumab govitecan (SG) in combination with cisplatin (Cis) in platinum (PLT)-naïve patients (pts) with metastatic urothelial cancer (mUC).

TPS581 Background: Cis-based combination chemotherapy regimens with gemcitabine or methotrexate, vinblastine, and doxorubicin are commonly used as initial treatment for mUC. However, only a fraction of pts maintain a durable response. Alternative Cis-based combinations with improved efficacy while maintaining tolerability are needed. SG is an antibody-drug conjugate (ADC) composed of an anti-trophoblast cell-surface antigen-2 (Trop-2) antibody coupled to SN-38 (a topoisomerase-I inhibitor) via a proprietary hydrolyzable linker. In vitro/in vivo urinary bladder cancer models suggest that the combination of SG and Cis resulted in additive antitumor activity over either agent alone (data on file). In the phase 2 registrational TROPHY-U-01 study, SG monotherapy resulted in a 27% objective response rate (ORR) and a median overall survival (OS) of 10.9 months with a manageable, mostly non–Cis-overlapping toxicity profile in heavily pretreated pts with mUC (Tagawa et al, J Clin Oncol. 2021). These results led to accelerated approval of SG by the FDA in 2021 for pts with locally advanced or mUC who previously received PLT-containing chemotherapy and a checkpoint inhibitor. We hypothesized that SG and Cis in combination may improve efficacy/safety over available first-line mUC regimens. TROPHY-U-01 Cohort 4 study will evaluate the safety, tolerability, and clinical activity of this novel combination. Methods: TROPHY-U-01 (NCT03547973) is a multicohort, open-label, global phase 2 trial. Cohort 4 will evaluate combination SG and Cis in PLT-naive pts with mUC or unresectable locally advanced disease. Key eligibility requirements include Eastern Cooperative Oncology Group performance status 0–1; no prior anticancer monoclonal antibody or ADC therapy within 4 weeks of study drug initiation; no history of active interstitial lung disease or noninfectious pneumonitis; adequate hematologic, hepatic, and renal function. Pts will be treated with Cis at 70 mg/m2 on day 1 of a 21-day cycle (if creatinine clearance [CrCl] ≥60 mL/min) or at a split dose of Cis at 35 mg/m2 on days 1 and 8 of a 21-day cycle (if CrCl 50-59 mL/min) followed by SG (5, 7.5, or 10 mg/kg) on days 1 and 8 of a 21-day cycle. The recommended phase 2 dose will be the dose in which ≤30% dose-limiting toxicities are noted in cycle 1. Combination therapy will continue for up to 6 cycles, followed by SG and avelumab maintenance given until progression. Prophylactic granulocyte colony-stimulating factor is not allowed in cycle 1 of the safety lead-in phase. Primary endpoint is ORR per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints include progression-free survival, duration of response, and clinical benefit rate per BICR and investigator assessment. OS and safety will be assessed. Enrollment is ongoing; ̃60 pts expected across ̃30 sites in North America and Europe. Clinical trial information: NCT03547973.

Impact of Human Epidermal Growth Factor Receptor 2 (HER2) Low Status in Response to Neoadjuvant Chemotherapy in Early Breast Cancer.

IntroductionIn clinical practice, there is a binary distinction between human epidermal growth factor receptor 2 (HER2)-positive and HER2-negative (HER2−) breast cancer (BC). However, within HER2− disease, there is significant heterogeneity. Particularly, HER2− tumors that express some level of HER2 by immunohistochemistry (IHC) score 1+ or 2+/in situ hybridization (ISH) non-amplified are currently defined as HER2-low. This subgroup has shown distinct biological features compared to HER2-zero (HER2-0) BC and additionally novel antibody-drug conjugate therapies have demonstrated a potential and promising activity in HER2-low BC population. This study aims to evaluate the impact of HER2-low status in response to neoadjuvant chemotherapy (NACT) in HER2− BC being HER2-low and HER2-0 status.Materials and methodsIn a single institution, we retrospectively reviewed clinical and pathological data of HER2 early-stage BC patients treated with NACT following definitive surgery from January 2015 to December 2020. Tumors with HER2 IHC 0 were classified as HER2-0 and IHC score 1+ and 2+/ISH non-amplified as HER2-low. The primary objective was to evaluate the rate of pathological complete response (pCR) using the definition of ypT0/Tis ypN0 according to HER2-low and HER2-0 subgroups. Secondary objectives were to evaluate biological features between the two subgroups, disease-free survival (DFS), and overall survival (OS). Pearson chi-square, Fisher’s exact, and Mann-Whitney tests were performed. The Kaplan-Meier method was used to plot DFS and OS curves. A p-value of <0.05 was considered statistically significant.ResultsA total of 72 patients with HER2 BC were included with a median age at diagnosis of 52.5 years and a median follow-up time of 35.5 months. Of patients, 56.9% had HER2-low disease and 43.1% had HER2-0 disease. Significant differences between the two subgroups were detected regarding hormonal receptor status and proliferation grade (Ki67). In the HER2-low subgroup, 70% of tumors were luminal-like and 64.5% of HER2-0 patients had triple-negative BC (p = 0.03). There were statistically significant differences regarding estrogen (p = 0.00) and progesterone (p = 0.02) receptors. The median Ki67 rate was higher in the HER2-0 subset (mean rank = 43.9) compared to HER2-low (mean rank = 30.9) and this difference was statistically significant (p = 0.00). HER2-low patients presented more stage III tumors (65.9%) and HER2-0 patients were mainly stage II (61.3%), and this was statistically relevant (p = 0.03). The prevalence of other clinical and pathological features was comparable between both groups. HER2-low subgroup achieved lower pCR rates (14.6% vs. 29.0%) but this difference was not statistically significant (p = 0.15). Similarly, there was no difference between the two subgroups regarding DFS (p = 0.97) and OS (p = 0.35), although the data were immature.ConclusionAs in prior studies, this study did not support a significant impact of HER2-low status on response to NACT in HER2− patients with early-stage BC. HER2-low patients had a lower pCR, which may suggest a worse response to classic chemotherapy regimen and may have clinical implications that should be further exploited. The prevalence of hormonal receptors in HER2-low tumors was consistent with previous data in the literature. Although retrospective, the data suggest that HER2-low tumors should be regarded as a distinct biological subtype and more research is warranted.

Molecular Mechanisms, Biomarkers and Emerging Therapies for Chemotherapy Resistant TNBC.

Triple-negative breast cancer (TNBC) is associated with high recurrence rates, high incidence of distant metastases, and poor overall survival (OS). Taxane and anthracycline-containing chemotherapy (CT) is currently the main systemic treatment option for TNBC, while platinum-based chemotherapy showed promising results in the neoadjuvant and metastatic settings. An early arising of intrinsic or acquired CT resistance is common and represents the main hurdle for successful TNBC treatment. Numerous mechanisms were uncovered that can lead to the development of chemoresistance. These include cancer stem cells (CSCs) induction after neoadjuvant chemotherapy (NACT), ATP-binding cassette (ABC) transporters, hypoxia and avoidance of apoptosis, single factors such as tyrosine kinase receptors (EGFR, IGFR1), a disintegrin and metalloproteinase 10 (ADAM10), and a few pathological molecular pathways. Some biomarkers capable of predicting resistance to specific chemotherapeutic agents were identified and are expected to be validated in future studies for a more accurate selection of drugs to be employed and for a more tailored approach, both in neoadjuvant and advanced settings. Recently, based on specific biomarkers, some therapies were tailored to TNBC subsets and became available in clinical practice: olaparib and talazoparib for BRCA1/2 germline mutation carriers larotrectinib and entrectinib for neurotrophic tropomyosin receptor kinase (NTRK) gene fusion carriers, and anti-trophoblast cell surface antigen 2 (Trop2) antibody drug conjugate therapy for heavily pretreated metastatic TNBC (mTNBC). Further therapies targeting some pathologic molecular pathways, apoptosis, miRNAS, epidermal growth factor receptor (EGFR), insulin growth factor 1 receptor (IGF-1R), and androgen receptor (AR) are under investigation. Among them, phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and EGFR inhibitors as well as antiandrogens showed promising results and are under evaluation in Phase II/III clinical trials. Emerging therapies allow to select specific antiblastics that alone or by integrating the conventional therapeutic approach may overcome/hinder chemoresistance.

Plasma cell leukemia: Retrospective review of cases at Monter Cancer Center/Northwell Health Cancer Institute, 2014-2019

Plasma cell leukemia (PCL) is an aggressive malignancy and an area of unmet need. The diagnostic criteria for PCL are in flux and the molecular basis of disease is complex. Due to its fulminant course and lack of prospective clinical trials in PCL, the optimal therapeutic approach remains controversial. “Novel therapy” in this manuscript refers to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). “Newer agents” refers to currently approved and investigational targeted therapies such as monoclonal antibodies (mAbs), example daratumumab (Dara), bi- or tri-specific antibodies, and antibody-drug conjugate therapies (ADCs). Novel therapy and use of newer agents borrowed from treatment advances in multiple myeloma (MM), is impacting PCL outcomes. Therefore, it is crucial to analyze effects of newer agents on PCL survival with respect to disease characteristics and specific treatment regimens used. In this retrospective study, we report outcomes of eight cases of PCL, primary and secondary, the prognostic factors in each case and the impact of different treatment regimens on overall survival (OS).

Antibody-drug conjugate therapies in multiple myeloma-what's next on the horizon?

Targeted immunotherapy has arisen over the past decade to the forefront of cancer care. Notably, targeted therapies such as antibody-drug conjugates (ADCs) are becoming more recognized for a novel approach in cancer treatment. The mechanism of action of ADCs incorporates a monoclonal antibody portion directed against the tumor cell antigen and attached to the tumoricidal portion via chemical linkage. The binding of the monoclonal antibody portion allows for tumor cell internalization of the ADC and precise release of the toxic payload within the cancer cell. Multiple myeloma (MM) is an incurable cancer for which belantamab mafodotin was the first-in-class ADC to achieve United States Food and Drug Administration (FDA) approval for treatment of this disease. Clinical trials are currently evaluating other ADCs in the treatment of MM. In this review, a look at the current ADCs being tested in MM clinical trials with a focus on those that are more promising and a potential next-in-line for FDA approval for treatment of MM is discussed.

Emerging immuno-oncology targets in Myelodysplastic Syndromes (MDS)

Approaches to immunologic therapies in myelodysplastic syndromes (MDS) have generally fallen into 2 categories: therapies that target immune effector cells and enhance or direct an antileukemic effect, and therapies which target immunological markers on MDS progenitors themselves. Examples of the former include immune checkpoint inhibitors, immunomodulatory therapies, and vaccines, among others, while examples of the latter include antibody-drug conjugate therapies and naked antibodies; while bispecific antibodies and modified T-cells (such as CAR-T therapies) bridge both therapeutic modalities. In this review, we will discuss the rationale for the above therapies, clinical results to date, and potential future directions for investigation.

ASCO 2021—an update on metastastic colorectal cancer

SummaryThe 2021 ASCO Annual Meeting provided updates on novel therapies in rare subgroups of metastatic colorectal cancer, such as immunotherapy in microsatellite instable colorectal cancer and antibody–drug conjugate therapy in HER2-positive disease. Furthermore, the concept of anti-EGFR rechallenge therapy has received additional momentum with data from the CHRONOS trial in regard to treating patients in later lines as well as how to integrate analysis of circulating tumor DNA in clinical decision-making.

Anti B-cell maturation antigen CAR T-cell and antibody drug conjugate therapy for heavily pretreated relapsed and refractory multiple myeloma.

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, California Health Care Foundation, The Donaghue Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from AbbVie, Aetna, America's Health Insurance Plans, Anthem, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Evolve Pharmacy, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Humana, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, uniQure, and United Healthcare. Beinfeld, Fluetsch, and Pearson are employed by ICER. Ollendorf received funding from ICER for work on this summary and reports consulting and other personal fees from EMD Serono, Amgen, Analysis Group, Aspen Institute/University of Southern California, GalbraithWight, Cytokinetics, Executive Insight, Sunovion, University of Colorado, World Health Organization, and Eli Lilly, unrelated to this work. Lee and McQueen received funding from ICER for work on this summary.

Antibody-Based Therapy in AML: Antibody–Drug Conjugates and Bispecific Agents

<h2>Introduction</h2> Remissions following therapy for acute myeloid leukemia (AML) are often not durable, and conventional treatments can have substantial toxicity. The last few years have witnessed an emergence of promising therapies for patients with AML. Antibody-based therapies can target leukemic cells via a variety of mechanisms. Conjugation of antibodies with cytotoxic agents or alteration of antibody segments to allow concurrent activation of T cells have transformed and expanded the therapeutic potential of antibody-based treatment. Identification and characterization of antigens specific to AML cells have helped to identify targets for antibody-drug conjugate (ADC) therapy. In addition, bispecific T cell engagers (BiTE) and dual-affinity retargeting (DART) therapies are emerging as therapeutically effective targeted immune-based treatment for patients with AML. Incorporating the target antigen-binding domain of an antibody, these molecules then engage and active the human immune system against leukemic cells expressing that target.

The ROR1 antibody-drug conjugate huXBR1-402-G5-PNU effectively targets ROR1+ leukemia

AbstractAntibody-drug conjugates directed against tumor-specific targets have allowed targeted delivery of highly potent chemotherapy to malignant cells while sparing normal cells. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal protein with limited expression on normal adult tissues and is overexpressed on the surface of malignant cells in mantle cell lymphoma, acute lymphocytic leukemia with t(1;19)(q23;p13) translocation, and chronic lymphocytic leukemia. This differential expression makes ROR1 an attractive target for antibody-drug conjugate therapy, especially in malignancies such as mantle cell lymphoma and acute lymphocytic leukemia, in which systemic chemotherapy remains the gold standard. Several preclinical and phase 1 clinical studies have established the safety and effectiveness of anti-ROR1 monoclonal antibody–based therapies. Herein we describe a humanized, first-in-class anti-ROR1 antibody-drug conjugate, huXBR1-402-G5-PNU, which links a novel anti-ROR1 antibody (huXBR1-402) to a highly potent anthracycline derivative (PNU). We found that huXBR1-402-G5-PNU is cytotoxic to proliferating ROR1+ malignant cells in vitro and suppressed leukemia proliferation and extended survival in multiple models of mice engrafted with human ROR1+ leukemia. Lastly, we show that the B-cell lymphoma 2 (BCL2)-dependent cytotoxicity of huXBR1-402-G5-PNU can be leveraged by combined treatment strategies with the BCL2 inhibitor venetoclax. Together, our data present compelling preclinical evidence for the efficacy of huXBR1-402-G5-PNU in treating ROR1+ hematologic malignancies.

Corneal Epitheliopathy Associated With Antibody-Drug Conjugates

This report highlights corneal epithelial changes in 3 patients receiving different antibody-drug conjugate (ADC) therapies that inhibit tubulin assembly: anetumab ravtansine for malignant pleural mesothelioma (Figure A), ado-trastuzumab emtansine for human epidermal growth factor receptor–positive ductal carcinoma of the breast (Figure B), and belantamab mafodotin for refractory myeloma (Figures C and D). The ADCs are a novel approach for treating cancer by using targeted monoclonal antibodies to direct cytotoxic payloads to malignant cells while reducing systemic toxicity.

Abstract 514: Specific anti-HER2 host immunity conferred by HER2-targeted antibody drug conjugate therapy and checkpoint blockade

Abstract Using HER2-targeted antibody drug conjugates (ADC), we tested the therapeutic efficacy, direct impact on cancer stem cells (CSCs), and potential added benefit when combined with PD-L1 blockade in immunocompetent mouse tumor models. Two murine mammary tumor models were used in this study: D2F2/E2, a cell line resulting from stable transfection of parental D2F2 murine mammary tumor cells with wild-type human HER2, and 4T1-HER2, derived from parental 4T1 by stable transduction with wild-type human HER2. We demonstrate that HER2-targeted ADC treatment induced both cellular and humoral anti-HER2 adaptive immune responses which effectively targeted both bulk tumor and cancer stem cells. We recently investigated induction of host immunity using a tumor re-challenge strategy in tumor free animals subjected to ADC or ADC + anti-PD-L1 therapy. D2F2/E2 tumor-bearing mice were treated with ADC or ADC + anti-PD-L1 to generate tumor free mice. These tumor free animals were re-challenged with the relevant tumor D2F2/E2 or irrelevant tumor WT 4T1 respectively. While all the tumor free animals re-challenged with WT 4T1 showed aggressive tumor growth, ADC-treated tumor free animals re-challenged with D2F2/E2 demonstrated significantly (p&amp;lt;0.0001) slower tumor growth compared with the age-matched naive mice, and this protection was significantly (p=0.0078) enhanced in ADC + anti-PD-L1-treated tumor free animals, resulting in completely rejection of the re-challenge and thus documenting immunological memory formation. B cell activation was obvious by the significant upregulation of Ki67 and GL7 CD86 on both CD45+CD19+ tumor-infiltration lymphocytes (TILs) and splenocytes. B cell differentiation was evident by the upregulation of GL7 on both TILs and splenocytes, as well as the expression of CD138 on splenotytes. We found that IgG1 was the predominant isotype in treated mice vs. IgG2a, IgG2b, IgG3, and ADC + anti-PD-L1 dual treatment drastically increased the amount of IgG1 in serum. In addition, ADC+ anti-PD-L1 dual treatment significantly increased the frequency of CD8+IFNγ+ cells in TILs. Both ADC alone (p=0.0004) and ADC+anti-PD-L1 dual treatment (p=0.01) significantly decreased CD4+FoxP3+ regulatory T cells. These results provide evidence that HER2-targeted ADC + anti-PD-L1 immunotherapy-induced B cell activation and differentiation along with the modulation of T cell subsets could confer host anti-HER2 immunity. Citation Format: You Qin, Hannah E. Dobson, Frank I. Comer, Alfred E. Chang, Max S. Wicha, Qiao Li. Specific anti-HER2 host immunity conferred by HER2-targeted antibody drug conjugate therapy and checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 514.

Treatment and prognosis of advanced triple-negative breast cancer patients with HER2-low expression: A 15-year retrospective study.

e13046 Background: There is some tumor defined HER2 1+ or 2+ by IHC and negative in FISH as HER2 low expression in common triple-negative breast cancer (TNBC). This subset is considered to be a new subtype of HER2-low BC, which might benefit from HER2-targeted antibody drug conjugate (ADC). Therefore, it could preliminarily understand on treatment status and treatment needs of HER2-low BC by analysis of the distribution, treatment patterns and prognosis of HER2-low BC in advanced TNBC. Methods: This was a retrospective study which included HR-negative, HER2 IHC 0/1+/2+ and FISH negative ABC patients (pts) diagnosed from June 2006 to September 2020, with recurrence and de novo metastatic cancer at a single institution in China. The cut-off date of follow-up was 31 December 2020. The baseline characteristics, first- and second-line therapies and the clinical outcomes were reported. Results: In total of 195 pts with complete follow-up data were included into final analysis. HR-negative, HER2 IHC 0 pts (triple negative, TN pts) were 61.5% (n = 120), and HR- negative, HER2 IHC 1 + / 2 + and FISH negative pts (HER2-low pts) were 38.5% (n = 75). The baseline characteristics and treatment patterns of HER2-low pts and TN pts were similar. The median age of pts at diagnosis was 48 years old while 54.4% pts were premenopausal. About 80% pts were recurrence, and 27.6% of them received neoadjuvant chemotherapy. The median disease-free interval (DFI) in early stage was 15.5 months, with 66.0% pts for DFI≥12 months. 56.4% of the pts presented with visceral metastasis. The most common sites of metastasis were lung (35.4%), lymph node (27.7%), soft tissue (24.1%), liver (20.5%), bone (20.5%), and brain (6.2%). The most commonly used regimens for first- and second-line were combination chemotherapy, which were 74.7% and 65.3%, respectively; paclitaxel (55.6%) and platinum (43.8%) were the most commonly used drugs for the first-line treatment. Only 14.4% and 3.6% pts received targeted combination therapy and immunotherapy in advanced setting, respectively. In TN and HER2-low ABC pts, the median PFS of first-line treatment were both 7.2 months, and the median OS was 17.2 months and 17.0 months, respectively. In DFI≥12 months and DFI&lt;12 months subgroup, the median PFS was 8.4 months vs. 4.7 months, with a median OS of 17.8 months vs. 14.4 months, respectively. No significant different was observed between HER2-low pts and TN pts. Conclusions: Based on this observational cohort study, there is no significant difference in the current treatment patterns and prognosis between HER2-low pts and TN pts. However, with the emergence of HER2-targeted ADC therapy, HER2-low ABC pts which were commonly defined as TNBC may benefit from these novel therapies. The recurrence subgroup with DFI≥12 months presented a trend of longer OS, suggesting the therapy mode and response in early stage should be considered in advanced TNBC treatment.

Reversible HER2 antibody-drug conjugate–induced ocular toxicity

PurposeTo report 3 cases of reversible epitheliopathy induced by A166—a human epidermal growth factor receptor (HER2)-targeted antibody-drug conjugate (ADC) therapy for resistant HER2 tumours. MethodsAdvanced HER2 tumour patients were enrolled in A166 phase I/II clinical trial using Bayesian logistic regression model dose escalation. Key exclusion criteria were ≥grade 2 (G2) corneal pathology, severe organ disease, and other cancer therapy within 4 weeks. Eye exams were performed at baseline, regularly scheduled intervals, and additionally upon A166-induced ocular symptoms. Topical therapy with autologous serum tears (ASTs) was implemented based on visual acuity, symptoms, and slit lamp exam. A166 was withheld if ≥G2 ocular toxicity developed; if status improved to ≤G1, A166 therapy was resumed. Visual acuity, corneal exam, and subjective comfort were recorded. ResultsAfter ≥2 cycles of A166, 6 eyes of 3/23 enrolled patients developed whorl pattern epitheliopathy suggestive of limbal stem cell (LSC) dysfunction requiring cessation of A166 despite positive tumour response. Patients 1 and 3 received 3.6 mg/kg A166 dose, and patient 2 received 3.0 mg/kg. Topical steroids (2/4 eyes) failed to improve epitheliopathy. Adding ASTs improved vision, ocular comfort, and whorl pattern epitheliopathy in 6/6 eyes within 3 weeks. Patient 1 continues to improve on ASTs; patient 2 withdrew from the study; and patient 3 resumed A166 therapy. ConclusionA166 precipitates LSC dysfunction-like epitheliopathy. Combination therapy including aggressive lubrication, withholding drug, and ASTs help reverse toxicity. Recognizing that ADC-induced epitheliopathy can respond to ocular management may enable cancer patients to continue lifesaving therapy.

HER2-targeted antibody-drug conjugate induces host immunity against cancer stem cells

We previously tested HER2-targeted antibody-drug conjugates (ADCs) in immunocompromised (SCID) mice, precluding evaluation of host immunity, impact on cancer stem cells (CSCs), and potential benefit when combined with PD-L1 blockade. In this study, we tested HER2-targeted ADC in two immunocompetent mouse tumor models. HER2-targeted ADC specifically inhibited the growth of HER2-expressing tumors, prolonged animal survival, and reduced HER2+ and PD-L1+ cells. ADC+ anti-PD-L1 antibody augmented therapeutic efficacy, modulated immune gene signatures, increased the number and function of CD3+ and CD19+ tumor-infiltrating lymphocytes (TILs), induced tumor antigen-specific immunological memory, stimulated B cell activation, differentiation, and IgG1 production both systemically and in the tumor microenvironment. In addition, ADC therapy modulated Tcell subsets and their activation in TILs. Furthermore, HER2-targeted ADC reduced the number and tumorigenicity of ALDHhi CSCs. This study demonstrates that HER2-targeted ADC effectively targets ALDHhi CSCs and this effect is augmented by co-administration of anti-PD-L1 antibody.

Data-Driven Discovery of Molecular Targets for Antibody-Drug Conjugates in Cancer Treatment.

Antibody-drug conjugate therapy has attracted considerable attention in recent years. Since the selection of appropriate targets is a critical aspect of antibody-drug conjugate research and development, a big data research for discovery of candidate targets per tumor type is outstanding and of high interest. Thus, the purpose of this study was to identify and prioritize candidate antibody-drug conjugate targets with translational potential across common types of cancer by mining the Human Protein Atlas, as a unique big data resource. To perform a multifaceted screening process, XML and TSV files including immunohistochemistry expression data for 45 normal tissues and 20 tumor types were downloaded from the Human Protein Atlas website. For genes without high protein expression across critical normal tissues, a quasi H-score (range, 0-300) was computed per tumor type. All genes with a quasi H − score ≥ 150 were extracted. Of these, genes with cell surface localization were selected and included in a multilevel validation process. Among 19670 genes that encode proteins, 5520 membrane protein-coding genes were included in this study. During a multistep data mining procedure, 332 potential targets were identified based on the level of the protein expression across critical normal tissues and 20 tumor types. After validation, 23 cell surface proteins were identified and prioritized as candidate antibody-drug conjugate targets of which two have interestingly been approved by the FDA for use in solid tumors, one has been approved for lymphoma, and four have currently been entered in clinical trials. In conclusion, we identified and prioritized several candidate targets with translational potential, which may yield new clinically effective and safe antibody-drug conjugates. This large-scale antibody-based proteomic study allows us to go beyond the RNA-seq studies, facilitates bench-to-clinic research of targeted anticancer therapeutics, and offers valuable insights into the development of new antibody-drug conjugates.

EV20‑sss‑vc/MMAF, an HER‑3 targeting antibody‑drug conjugate displays antitumor activity in liver cancer.

Liver cancer (LC) is an aggressive disease with a markedly poor prognosis. Therapeutic options are limited, and, until recently the only FDA‑approved agent for first‑line treatment of patients with LC was the multi‑kinase inhibitor sorafenib, which exhibits limited activity and an increased overall survival(OS) of only 3months over placebo. Therefore, the development of alternative therapeutic molecules for the treatment of LC is an urgent medical need. Antibody‑drug conjugates(ADCs) are an emerging class of novel anticancer agents, which have been developed recently for the treatment of malignant conditions, including LC, and are being studied in preclinical and clinical settings. Our group has recently generated an ADC [EV20/monomethyl auristatinF(MMAF)] by coupling the HER3 targeting antibody(EV20) to MMAF via a non‑cleavable maleimidocaproyl linker. This ADC was revealed to possess potent therapeutic activity in melanoma and breast carcinoma. In the present study, using western blot and flow cytometric analysis, it was reported that HER‑3 receptor was highly expressed in LC and activated by its ligand NRG‑1β in a panel of LC cell lines, thus indicating that this receptor may serve as a suitable target for ADC therapy. A novel ADC [EV20‑sss‑valine‑citrulline (vc)/MMAF] was generated, in which the cytotoxic payload MMAF was site‑specifically coupled to an engineered variant of EV20 via a vc cleavable linker. Cytotoxicity assays were performed to investigate invitro antitumor activity of EV20‑sss‑vc/MMAF and it was compared to EV20/MMAF, which revealed only modest activity in LC.EV20‑sss‑vc/MMAF exhibited a significant cell killing activity in several LC cell lines. Additionally, invivo xenograft experiments revealed that EV20‑sss‑vc/MMAF inhibited growth of LC tumors. The present data indicated that EV20‑sss‑vc/MMAF is a worthy candidate for the treatment of HER‑3 positive LC.