Strategies for Mitigating Antibody-Drug Conjugate Related Adverse Events for Precision Therapy
Antibody-drug conjugates (ADCs) have been revolutionary in improving personalized therapy of cancer. Through combining monoclonal antibodies, which are targeted to tumor-specific antigens, and cytotoxic agents, ADCs lead to selective delivery of active components, also called payloads, to cancerous cells while sparing healthy body cells from possible collateral damage. Adverse events, however, can still develop because of early release of the payload or cross-expression of targets by normal cells leading to collateral damage. In this review, we elaborate on the common and serious adverse events for the currently US Food an...
Source: The Cancer Journal - November 1, 2022 Category: Cancer & Oncology Tags: Review Articles Source Type: research
Antibody Drug Conjugates in Multiple Myeloma
Antibody-drug conjugates (ADCs) have emerged as a treatment option for patients with relapsed/refractory multiple myeloma with the regulatory approval of the first-in-class B-cell maturation antigen (BCMA) ADC belantamab mafodotin. Other BCMA and non-BCMA ADCs are currently in clinical development. Whereas ADCs allow antigen-specific delivery of a chemomoiety to myeloma cells, on-target and off-target effects related to antigen target, antibody, linker, and chemomoiety can also limit these approaches. We review the clinical development of belantamab mafodotin and ongoing efforts to enhance its efficacy while mitigating ocu...
Source: The Cancer Journal - November 1, 2022 Category: Cancer & Oncology Tags: Review Articles Source Type: research
Evolving Landscape of Antibody Drug Conjugates in Lymphoma
Despite the curative potential of autologous transplantation and chimeric antigen receptor T cells in lymphoma, many patients are ineligible, or their disease progresses after these treatments. In this context, antibody drug conjugates (ADCs) have demonstrated very promising efficacy in lymphomas. Antibody drug conjugates are monoclonal antibodies covalently linked to a cytotoxic drug. Because of its highly specific targeting abilities and powerful killing effects, it has become a promising technology for developing anticancer drugs in recent years. The US Food and Drug Administration has approved 14 ADCs since Mylotarg (g...
Source: The Cancer Journal - November 1, 2022 Category: Cancer & Oncology Tags: Review Articles Source Type: research
Toxicities From Antibody-Drug Conjugates
Antibody-drug conjugates are becoming increasingly important in the treatment of many cancer types. The 3 main structural components—antibody, linker, and payload—each contribute to the toxicity profiles of these drugs. In addition to cytopenias and gastrointestinal adverse effects attributed to the chemotherapy payloads, each drug has specific toxicities that are not commonly described in oncology. Ocular, pulmonary, dermatologic, and neurologic toxicities are particularly nuanced. This review provides a framework for clinicians to analyze current and future antibody-drug conjugates and a description of the unique mon...
Source: The Cancer Journal - November 1, 2022 Category: Cancer & Oncology Tags: Review Articles Source Type: research
Antibody-Drug Conjugates and Tissue-Agnostic Drug Development: An Update
Antibody-drug conjugates (ADCs) deliver effective medications to tumor cells that express specific antigens, maximizing efficacy and reducing adverse effects. Because ado-trastuzumab emtansine was approved in 2013, 5 ADCs received US Food and Drug Administration approval for solid tumor treatment. Technical advancements in the development of each component of ADCs allowed novel monoclonal antibodies, linkers, and payloads to increase drug transport to malignant cells and drug activity even in cancers with heterogeneous antigen expression. In addition, several ADCs are in development using new molecular targets expressed ac...
Source: The Cancer Journal - November 1, 2022 Category: Cancer & Oncology Tags: Review Articles Source Type: research
Antibody-Drug Conjugates in Myeloid Leukemias
Targeted therapy in oncology brings with it the promise to maximize cancer cell cytotoxicity with minimal off-target effects. Antibody-drug conjugates (ADCs), an important group of such targeted agents, consist of a monoclonal antibody conjugated to a potent cytotoxic drug. In the field of leukemia, ADCs form an important component of therapeutic arsenal through the use of gemtuzumab ozogamicin in acute myeloid leukemia and inotuzumab ozogamicin (InO) in B-cell acute lymphoblastic leukemia, 2 approved agents. A recombinant fusion protein, tagraxofusp, which function similar to ADC, has gained approval for therapy in blasti...
Source: The Cancer Journal - November 1, 2022 Category: Cancer & Oncology Tags: Review Articles Source Type: research
The Role of Radiolabeled Monoclonal Antibodies in Cancer Imaging and ADC Treatment
Antibody-drug conjugates (ADCs) are designed to deliver cytotoxic payloads to distinctive target-expressing cancer cells. Following internalization, the ADCs are routed to different compartments in the cells, where cleavage of the linker causes release of the cytotoxic cargo. With such a delivery system, more effective payloads can reach cancer cells, allowing for more efficient treatment and dosing schedule. The monoclonal antibody (mAb) component of ADC plays a crucial role in the effective targeting of cancer cell–specific antigens while minimizing binding to normal cells. Often, the same mAbs used in ADCs can be labe...
Source: The Cancer Journal - November 1, 2022 Category: Cancer & Oncology Tags: Review Articles Source Type: research
Antibody-Drug Conjugates in Breast Cancer: What Is Beyond HER2?
The therapeutic landscape of patients with breast cancer has changed significantly with the introduction of antibody-drug conjugates (ADCs). Although human epidermal growth factor receptor 2 (HER2) has been the centerpiece of ADC development, potentially any surface antigen with differential expression between tumor and normal cells may be suitable for targeting with ADCs. Exploration of new targets is critical to expand the fraction of patients who can benefit from ADCs. Sacituzumab govitecan, an anti–trophoblast cell surface antigen 2 ADC, is the only non–anti-HER2 ADC approved for breast cancer to date, with several...
Source: The Cancer Journal - November 1, 2022 Category: Cancer & Oncology Tags: Review Articles Source Type: research
Antibody Drug Conjugates in Lung Cancer
An antibody-drug conjugate (ADC) comprises a monoclonal antibody that is specific to a tumor cell protein, bound to a cytotoxic agent, known as the payload. The use of ADCs is already common practice in several cancers, thanks to their efficacy and potentially more manageable toxicity profile, resulting from the release of the cytostatic payload directly in the tumors. Currently, early-phase trials of ADCs in non–small cell lung cancer are rapidly gaining ground, with promising results targeting HER2 (human epidermal growth factor 2), HER3, TROP2 (trophoblast cell surface antigen 2), MET, CEACAM5 (carcinoembryonic antige...
Source: The Cancer Journal - November 1, 2022 Category: Cancer & Oncology Tags: Review Articles Source Type: research
Antibody-Drug Conjugates in Breast Cancer: Spotlight on HER2
This article reviews the history of HER2-directed ADCs in breast cancer as well as ongoing ADCs in development. (Source: The Cancer Journal)
Source: The Cancer Journal - November 1, 2022 Category: Cancer & Oncology Tags: Review Articles Source Type: research
Recent Advances in the Development of Antibody-Drug Conjugates in Urothelial Cancer
Antibody-drug conjugates (ADCs) have joined the armamentarium against urothelial cancer (UC) as an effective therapy option. Since 2019, the US Food and Drug Administration has approved 2 ADCs for advanced previously treated UC: enfortumab vedotin, which targets nectin-4 and sacituzumab govitecan, which targets trophoblast cell-surface antigen 2. These ADCs are now being tested in earlier disease settings and in previously untreated patients. Furthermore, novel ADCs (e.g., anti–HER-2) are being tested in the clinic and show promising clinical benefit. The next frontier is to understand the mechanisms of resistance and re...
Source: The Cancer Journal - November 1, 2022 Category: Cancer & Oncology Tags: Review Articles Source Type: research
Human Papillomavirus–Directed Therapeutics for Human Papillomavirus–Associated Oropharyngeal Cancer
Despite the availability of prophylactic human papillomavirus (HPV) vaccines, there is a growing incidence of HPV-associated head and neck squamous cell carcinomas (HPV-HNSCC) worldwide. The viral etiology of HPV-HNSCC provides an opportunity to develop personalized immune-based therapies, which target the unique viral- or tumor-specific proteins. Novel HPV-targeted immunotherapeutic approaches in clinical development are reviewed. Early results from these trials highlight new opportunities and potential challenges ahead. Immunotherapies for HPV-associated HNSCCs will require a tailored combinatorial approach based on pree...
Source: The Cancer Journal - September 1, 2022 Category: Cancer & Oncology Tags: Review Articles Source Type: research
STING Agonists in Head and Neck Squamous Cell Carcinoma
Despite the development of new treatment paradigms and improved biologic understanding of head and neck squamous cell carcinoma (HNSCC), therapeutic resistance remains a substantial problem, and novel treatment approaches are needed. Stimulator of interferon genes (STING) is a critical regulator of the antitumor response through regulation of both immune-dependent and tumor-intrinsic mechanisms. As such, the STING pathway has emerged as a rational pharmacologic target leading to the development of multiple STING agonists. These compounds have impressive preclinical efficacy as single agents and with PD-1 (programmed death-...
Source: The Cancer Journal - September 1, 2022 Category: Cancer & Oncology Tags: Review Articles Source Type: research
Aurora Kinases as Therapeutic Targets in Head and Neck Cancer
The Aurora kinases (AURKA and AURKB) have attracted attention as therapeutic targets in head and neck squamous cell carcinomas. Aurora kinases were first defined as regulators of mitosis that localization to the centrosome (AURKA) and centromere (AURKB), governing formation of the mitotic spindle, chromatin condensation, activation of the core mitotic kinase CDK1, alignment of chromosomes at metaphase, and other processes. Subsequently, additional roles for Aurora kinases have been defined in other phases of cell cycle, including regulation of ciliary disassembly and DNA replication. In cancer, elevated expression and acti...
Source: The Cancer Journal - September 1, 2022 Category: Cancer & Oncology Tags: Review Articles Source Type: research
Mitotic Checkpoints and the Role of WEE1 Inhibition in Head and Neck Squamous Cell Carcinoma
The WEE1 kinase family plays a crucial role in cell cycle regulation and DNA damage response pathways in malignant cells. Inhibition of WEE1 effectively overrides G2 cell cycle arrest and results in the accumulation of extensive DNA damage within dividing cells, potentiating mitotic catastrophe and cell death. As such, the development of WEE1 inhibitors as antineoplastic therapeutics has gained increasing interest in recent years. In particular, the role of WEE1 inhibitors for treatment of head and neck squamous cell carcinomas remains an area of active research with both preclinical and clinical studies investigating thei...
Source: The Cancer Journal - September 1, 2022 Category: Cancer & Oncology Tags: Review Articles Source Type: research
