Antibody-drug Conjugate Research Articles

EP.06B.18 Biomarker Landscape of Antibody-Drug Conjugates and Bispecific Antibodies in Clinical Trials for Lung Cancer

EP.06B.18 Biomarker Landscape of Antibody-Drug Conjugates and Bispecific Antibodies in Clinical Trials for Lung Cancer

Clinical management of a patient with non-triple-negative breast cancer who converts to a triple-negative subtype at recurrence.

The management of patients with advanced breast cancer is becoming increasingly complex compared to the past, mainly due to numerous therapeutic innovations introduced in the current therapeutic scenario. At the time of metastatic disease diagnosis, as indicated by the guidelines, it is important to perform a biopsy of the metastatic sites to optimize choices and expand therapeutic options. Approximately 25-45% of patients who experience a recurrence of the primary tumor lose hormone receptor expression: in this context, solid data comes from a subanalysis of the randomized clinical trial ASCENT, in which the benefit of a treatment with antibody-drug conjugate sacituzumab govitecan is also confirmed in case of non-triple negative breast cancer at diagnosis that subsequently convert to a triple negative subtype. The case reported below is representative of this clinical situation.

177 (PB165): ZW251, a novel glypican-3-targeting antibody-drug conjugate bearing a topoisomerase I inhibitor payload demonstrates compelling preclinical activity in hepatocellular carcinoma models

177 (PB165): ZW251, a novel glypican-3-targeting antibody-drug conjugate bearing a topoisomerase I inhibitor payload demonstrates compelling preclinical activity in hepatocellular carcinoma models

6 Oral: ZW220, a NaPi2b-directed topoisomerase I inhibitor Antibody-Drug Conjugate, demonstrates compelling preclinical activity in NSCLC, ovarian and uterine cancer models, with a favorable toxicology profile in non-human primates

6 Oral: ZW220, a NaPi2b-directed topoisomerase I inhibitor Antibody-Drug Conjugate, demonstrates compelling preclinical activity in NSCLC, ovarian and uterine cancer models, with a favorable toxicology profile in non-human primates

Revolutionary breakthrough unveiled: The combination of antibody-drug conjugates and immune checkpoint blockade sheds new light on advanced urothelial carcinoma

Revolutionary breakthrough unveiled: The combination of antibody-drug conjugates and immune checkpoint blockade sheds new light on advanced urothelial carcinoma

ME15 Antibody-drug conjugate and novel therapy in lung cancer

ME15 Antibody-drug conjugate and novel therapy in lung cancer

MO19-2 Clinical outcome of treatment rechallenge with HER2-directed antibody-drug conjugate in metastatic breast cancer

MO19-2 Clinical outcome of treatment rechallenge with HER2-directed antibody-drug conjugate in metastatic breast cancer

Trophoblast cell surface antigen-2: a promising new biomarker and potential therapeutic target in penile squamous cell carcinoma.

To evaluate the potential utility of antibody-drug conjugates targeting trophoblast cell surface antigen-2 (TROP-2) in patients with primary penile squamous cell carcinoma (PSCC), patients with recurrence (REC cohort), and patient-matched distant metastases (MET cohort), and to assess the potential use of TROP-2 as a predictive non-invasive biomarker in PSCC. A cohort comprising a PRIM (n = 37), REC (n = 5) and MET subcohort (n = 7), with MET including lymph node and lung metastases, was analysed using quantitative real-time PCR, ELISA and immunohistochemical staining with evaluation of H-score. TROP-2 mRNA and serum protein levels were significantly increased in primary and recurrent PSCC compared to cancer-free controls (both P < 0.001). Immunohistochemical analysis revealed that most of the PRIM cohort (n = 34/37, median H-score 260, interquartile range [IQR] 210-300), as well as all patients in the REC (median [IQR] H-score 200 [165-290]) and MET cohorts (median [IQR] H-score 280 [260-300]) exhibited moderate to strong membranous TROP-2 expression. Additionally, The H-score (membranous TROP-2 expression) was positively correlated with TROP-2 mRNA (ρ = 0.69, P < 0.0001, R2 = 0.70) and protein levels (ρ = 0.86, P < 0.0001, R2 = 0.59), indicating its potential as a non-invasive biomarker in PSCC. In summary, our results support further studies on TROP-2 as a diagnostic and therapeutic target in primary, recurrent and metastatic PSCC.

165 (PB153): NEXUS-01, a phase 1 study of LY4052031, an antibody-drug conjugate targeting Nectin-4 in participants with advanced or metastatic urothelial carcinoma or other solid tumors (Trial in Progress)

165 (PB153): NEXUS-01, a phase 1 study of LY4052031, an antibody-drug conjugate targeting Nectin-4 in participants with advanced or metastatic urothelial carcinoma or other solid tumors (Trial in Progress)

Novel bispecific antibody-drug conjugate targeting PD-L1 and B7-H3 enhances antitumor efficacy and promotes immune-mediated antitumor responses

BackgroundAntibody-drug conjugates (ADCs) offer a promising approach, combining monoclonal antibodies with chemotherapeutic drugs to target cancer cells effectively while minimizing toxicity.MethodsThis study examined the therapeutic efficacy and potential mechanisms of...

182 (PB170): Results from a phase 1/2, first-in-human, dose escalation and dose expansion study of an investigational anti-ADAM9 antibody-drug conjugate IMGC936 in patients with advanced solid tumors

182 (PB170): Results from a phase 1/2, first-in-human, dose escalation and dose expansion study of an investigational anti-ADAM9 antibody-drug conjugate IMGC936 in patients with advanced solid tumors

Review of Antibody-Drug Conjugates

Review of Antibody-Drug Conjugates

Strategies for the treatment of hormone receptor-positive HER2-low breast cancer based on clinical practice: a round table discussion.

Human epidermal growth factor receptor 2 (HER2)-low breast cancer is a newly identified targetable subset of breast tumors, and its clinical characteristics and treatment strategies are controversial. The emergence of novel anti-HER2 antibody-drug conjugate (ADC) has brought promising approaches for HER2-low breast cancer treatment. Several clinical trials have validated the efficacy and safety of trastuzumab deruxtecan (T-Dxd) in HER2-low breast cancer at different treatment settings. The treatment timing, candidate identification, long-term management, and overcoming drug resistance are crucial questions to improve breast cancer patient survival. Here we present a clinical case of hormone receptor-positive (HR+) HER2-low breast cancer patient who experienced neoadjuvant chemotherapy, surgery, adjuvant, and first-line endocrine therapy with limited effectiveness. After the treatment failure of CDK4/6 inhibitors, the utilization of T-Dxd brought a long-term disease response and tolerable low toxicities. In this round table discussion, we summarized opinions and recommendations from breast cancer surgeons and oncologists on treatment strategies for this patient. The discussion mainly focused on the precise diagnosis of HER2-low breast cancer, treatment design at different disease status, regimens selection according to drug response, strategies consideration for overcoming drug resistance and the management of adverse events in long-term survival. These opinions would provide critical insights to improve HER2-low breast cancer treatment and offer valuable suggestions for clinical practice.

Fully Automated Artificial Intelligence Solution for Human Epidermal Growth Factor Receptor 2 Immunohistochemistry Scoring in Breast Cancer: A Multireader Study.

The proven efficacy of human epidermal growth factor receptor 2 (HER2) antibody-drug conjugate therapy for treating HER2-low breast cancers necessitates more accurate and reproducible HER2 immunohistochemistry (IHC) scoring. We aimed to validate performance and utility of a fully automated artificial intelligence (AI) solution for interpreting HER2 IHC in breast carcinoma. A two-arm multireader study of 120 HER2 IHC whole-slide images from four sites assessed HER2 scoring by four surgical pathologists without and with the aid of an AI HER2 solution. Both arms were compared with high-confidence ground truth (GT) established by agreement of at least four of five breast pathology subspecialists according to ASCO/College of American Pathologists (CAP) 2018/2023 guidelines. The mean interobserver agreement among GT pathologists across all HER2 scores was 72.4% (N = 120). The AI solution demonstrated high accuracy for HER2 scoring, with 92.1% agreement on slides with high confidence GT (n = 92). The use of the AI tool led to improved performance by readers, interobserver agreement increased from 75.0% for digital manual read to 83.7% for AI-assisted review, and scoring accuracy improved from 85.3% to 88.0%. For the distinction of HER2 0 from 1+ cases (n = 58), pathologists supported by AI showed significantly higher interobserver agreement (69.8% without AI v 87.4% with AI) and accuracy (81.9% without AI v 88.8% with AI). This study demonstrated utility of a fully automated AI solution to aid in scoring HER2 IHC accurately according to ASCO/CAP 2018/2023 guidelines. Pathologists supported by AI showed improvements in HER2 IHC scoring consistency and accuracy, especially for distinguishing HER2 0 from 1+ cases. This AI solution could be used by pathologists as a decision support tool for enhancing reproducibility and consistency of HER2 scoring and particularly for identifying HER2-low breast cancers.

Imaged Capillary Isoelectric Focusing Coupled to High-Resolution Mass Spectrometry (icIEF-MS) for Cysteine-Linked Antibody-Drug Conjugate (ADC) Heterogeneity Characterization Under Native Condition.

Native mass spectrometry (nMS) is a cutting-edge technique that leverages electrospray ionization MS (ESI-MS) to investigate large biomolecules and their complexes in solution. The goal of nMS is to retain the native structural features and interactions of the analytes during the transition to the gas phase, providing insights into their natural conformations. In biopharmaceutical development, nMS serves as a powerful tool for analyzing complex protein heterogeneity, allowing for the examination of non-covalently bonded assemblies in a state that closely resembles their natural folded form. Herein, we present an imaged capillary isoelectric focusing-MS (icIEF-MS) workflow to characterize cysteine-linked antibody-drug conjugate (ADC) under native conditions. Two ADCs were analyzed: a latest generation cysteine-linked ADC polatuzumab vedotin and the first FDA-approved cysteine-linked ADC brentuximab vedotin. This workflow benefits from a recently developed icIEF system that is MS-friendly and capable of directly coupling to a high-sensitivity MS instrument. Results show that the icIEF separation is influenced by both drug payloads and the post-translational modifications (PTMs), which are then promptly identified by MS. Overall, this native icIEF-MS method demonstrates the potential to understand and control the critical quality attributes (CQAs) that are essential for the safe and effective use of ADCs.

Antibody-Drug Conjugates and Their Potential in the Treatment of Patients with Biliary Tract Cancer.

Background: Biliary tract cancers (BTCs) are aggressive in nature, often presenting asymptomatically until they are diagnosed at an advanced stage. Surgical resection or liver transplantation are potential curative options. However, a large proportion of patients present with incurable locally advanced or metastatic disease and most of these patients are only eligible for palliative chemotherapy or best supportive care. More recently, targeted therapies have proven beneficial in a molecularly selected subgroup of patients with cholangiocarcinoma who have progressed on previous lines of systemic treatment. However, only a minority of patients with BTCs whose tumours harbour specific molecular alterations can access these therapies. Methods: In relation to ADCs, studies regarding use of antibody-drug conjugates in cancer, particularly in BTCs, were searched in Embase (1974 to 2024) and Ovid MEDLINE(R) (1946 to 2024) to obtain relevant articles. Examples of current clinical trials utilising ADC treatment in BTCs were extracted from the ClinicalTrials.gov trial registry. Conclusions: Overall, this review has highlighted that ADCs have shown encouraging outcomes in cancer therapy, and this should lead to further research including in BTCs, where treatment options are often limited. The promising results observed with ADCs in various cancers underscore their potential as a transformative approach in oncology, warranting continued exploration and development and the need for education on the management of their specific toxicities. By addressing current challenges and optimising ADC design and application, future studies could potentially improve treatment outcomes for patients with BTCs and beyond, potentially in both early and advanced stage settings.

CD37 in acute myeloid leukemia: a novel surface target for drug delivery

AbstractAcute myeloid leukemia (AML) is the most common and lethal leukemia in adults. AML consists of many genetic subtypes, which limits broad applicability of targeted therapy. We discovered that the hematopoiesis-restricted tetraspanin CD37 is expressed on all primary AML blasts and thus may represent a common therapeutic target for AML regardless of subtype. We demonstrate that the internalization properties of CD37 are distinct in AML blasts when compared with normal blood cells, and that CD37 rapidly accumulates inside AML blasts via dynamin-dependent endocytosis. Our work revealed that the clinically relevant anti-CD37 antibody–drug conjugate (ADC) Debio 1562 (αCD37-DM1) is highly cytotoxic to AML blasts, but not normal hematopoietic stem cells. We found that αCD37-DM1 improved clinical outcomes and overall survival in multiple in vivo models of AML. Together, these data demonstrate that targeting CD37 with an ADC such as αCD37-DM1 is a feasible and promising therapeutic option for the treatment of AML.

Meta-Analysis of Age, Sex, and Race Disparities in the Era of Contemporary Urothelial Carcinoma Treatment

Background: Urothelial carcinoma (UC) is one of the most common cancers diagnosed worldwide. However, minority populations, such as female, elder, and Black patients, may have disparate outcomes and are commonly neglected in randomized prospective trials. This review aims to study the relationship between age, sex, and race on urothelial cancer prognosis, particularly focusing on contemporary therapy and its effect on overall survival. Methods: Phase III prospective trials since 2016 of immune checkpoint inhibitors, antibody-drug conjugates, or targeted therapies in urothelial carcinoma were identified from PubMed. Trials that did not report on survival by race, sex, or age distribution were excluded, and remaining trials (n = 17) were compared by subgroup. Results: Women were reported to have inferior OS on investigational agents compared to men in 9/17 trials. In a meta-analysis, women had inferior OS to men (OR 0.89 [95% CI: 0.78–0.99]; p = 0.04). Asian/Pacific Islander patients had inferior outcomes to White patients on investigational agents in 3/5 trials. In a meta-analysis, OS was not significant by race (OR 1.18 [0.90–1.46], p = 0.38). Black patients composed &lt;2% of all trial patients, and no subgroup data were reported. Both 65 (n = 7) and 75 (n = 2) were reported as age cut-offs in trial subgroups, and survival data were mixed. Conclusions: Women in UC trials may have inferior survival outcomes to men. Racial diversity was poor and thus limited any conclusions on survival disparities.

Targeting GPRC5D for multiple myeloma therapy.

Given its nearly ubiquitous expression on plasma cells and limited expression on essential normal tissue, the G protein-coupled receptor class C group 5 member D (GPRC5D) presents a promising opportunity for utilization as an immunotherapy target in multiple myeloma (MM). The therapeutic strategies targeting GPRC5D, such as bispecific antibodies (BsAbs), chimeric antigen receptor (CAR) T cells, and antibody-drug conjugates (ADCs), have been prominently emphasized in relapsed/refractory MM (R/R MM) in recent years. Further clinical trials are necessary to confirm the long-term efficacy of GPRC5D-targeting immunotherapies alone, explore their potentials co-targeting with other specific antigens, or investigate their combinations with existing treatments to overcome MM resistance. This review provides an overview of current research progress in GPRC5D, encompassing its biological characteristics and translational journey from laboratory to clinical application.

Antibody–drug conjugates and immune checkpoint inhibitors in cancer treatment: a systematic review and meta-analysis

Although antibody–drug conjugate (ADC) or immune checkpoint inhibitors (ICIs) alone fosters hope for the treatment of cancer, the effect of single drug treatment is limited and the safety profile of ADC and ICI therapy remains unclear. This meta-analysis aimed to examine the efficacy and safety of the combination of ADC and ICI therapy. This study type is a systematic review and meta-analysis. Literature retrieval was carried out through PubMed, Embase, Cochrane from inception to Jun. 5, 2024. Then, after data extraction, overall response rate (ORR) and adverse effects (AEs) were used to study its efficiency and safety. Publication bias was also calculated through Funnel plot, Begg's Test and Egger's test. Heterogeneity was investigated through subgroup and sensitivity analysis. The research protocol was registered with the PROSPERO (CRD42023375601). A total of 12 eligible clinical studies with 584 patients were included. The pooled ORR was 58% (95%CI 46%, 70%). Subgroup analysis showed an ORR of 77% (95%CI 63%, 91%) in classical Hodgkin lymphoma (cHL) and an ORR of 73% (95%CI 56%, 90%) in non-Hodgkin lymphoma (NHL). The most common AEs was peripheral neuropathy (38.0%). Meanwhile, AEs on skin (13.1–20.0%) and digestive system (9.0–36.0%) was hard be overlooked. ADC + ICI therapy may be recommended in cancer treatment, especially in cHL and NHL. However, strategies to manage toxicities warranted further exploration.