Antibody-Drug Conjugates in Hematologic Malignancies

2013 ◽  
pp. e108-e113
Author(s):  
Lori A. Leslie ◽  
Anas Younes
Keyword(s):  
Hematologic Malignancies ◽  
Cytotoxic Agents ◽  
Clinical Value ◽  
Suppressor Activity ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Tumor Suppressor Activity ◽  
Cytotoxic Molecules ◽  
Early Phase Clinical Trials ◽  
Antibody Drug

Antibody-drug conjugates (ADCs) are agents composed of a monoclonal antibody linked to cytotoxic molecules. By specifically delivering cytotoxic agents to cells expressing surface antigens of interest, ADC technology allows for the targeted use of highly toxic agents resulting in increased efficacy against malignant cells and decreased damage to normal tissue. Effector agents can be small molecules, radioisotopes, proteins, or bacterially derived toxins. Over the past several decades, ADCs have been evaluated in a variety of preclinical models of hematologic malignancies, as well as early-phase clinical trials with limited success. More recently, advancements in linkage technology, improvements in cytotoxin selection, and use of smaller conjugates containing partial rather than complete antibodies have drastically improved the potential clinical value of ADCs. In the future, ADC technology may be used to restore tumor suppressor activity, target the microenvironment, or replace nonfunctional enzymes. In this review we will discuss select ADCs in various stages of development for use in hematologic malignancies including lymphoma, multiple myeloma, and leukemia.

scholarly journals Antibody–Drug Conjugates for the Treatment of Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2898
Author(s):  
Chiara Corti ◽  
Federica Giugliano ◽  
Eleonora Nicolò ◽  
Liliana Ascione ◽  
Giuseppe Curigliano
Keyword(s):  
Breast Cancer ◽  
Bystander Effect ◽  
Metastatic Breast ◽  
Therapeutic Index ◽  
Cytotoxic Agents ◽  
Target Antigen ◽  
Her2 Positive ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

Metastatic breast cancer (BC) is currently an incurable disease. Besides endocrine therapy and targeted agents, chemotherapy is often used in the treatment of this disease. However, lack of tumor specificity and toxicity associated with dose exposure limit the manageability of cytotoxic agents. Antibody–drug conjugates (ADCs) are a relatively new class of anticancer drugs. By merging the selectivity of monoclonal antibodies with the cytotoxic properties of chemotherapy, they improve the therapeutic index of antineoplastic agents. Three core components characterize ADCs: the antibody, directed to a target antigen; the payload, typically a cytotoxic agent; a linker, connecting the antibody to the payload. The most studied target antigen is HER2 with some agents, such as trastuzumab deruxtecan, showing activity not only in HER2-positive, but also in HER2-low BC patients, possibly due to a bystander effect. This property to provide a cytotoxic impact also against off-target cancer cells may overcome the intratumoral heterogeneity of some target antigens. Other cancer-associated antigens represent a strategy for the development of ADCs against triple-negative BC, as shown by the recent approval of sacituzumab govitecan. In this review, we discuss the current landscape of ADC development for the treatment of BC, as well as the possible limitations of this treatment.

scholarly journals Pharmacologic Considerations in the Disposition of Antibodies and Antibody-Drug Conjugates in Preclinical Models and in Patients

Antibodies ◽  
2019 ◽  
Vol 8 (1) ◽  
pp. 3 ◽  
Author(s):  
Andrew T. Lucas ◽  
Ryan Robinson ◽  
Allison N. Schorzman ◽  
Joseph A. Piscitelli ◽  
Juan F. Razo ◽  
...  
Keyword(s):  
Cytotoxic Agents ◽  
Clinical Use ◽  
Individual Agent ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Rational Development ◽  
Patient Variables ◽  
Tumor Delivery ◽  
Agent Characteristics ◽  
Antibody Drug

The rapid advancement in the development of therapeutic proteins, including monoclonal antibodies (mAbs) and antibody-drug conjugates (ADCs), has created a novel mechanism to selectively deliver highly potent cytotoxic agents in the treatment of cancer. These agents provide numerous benefits compared to traditional small molecule drugs, though their clinical use still requires optimization. The pharmacology of mAbs/ADCs is complex and because ADCs are comprised of multiple components, individual agent characteristics and patient variables can affect their disposition. To further improve the clinical use and rational development of these agents, it is imperative to comprehend the complex mechanisms employed by antibody-based agents in traversing numerous biological barriers and how agent/patient factors affect tumor delivery, toxicities, efficacy, and ultimately, biodistribution. This review provides an updated summary of factors known to affect the disposition of mAbs/ADCs in development and in clinical use, as well as how these factors should be considered in the selection and design of preclinical studies of ADC agents in development.

scholarly journals Antibody–Drug Conjugates for the Treatment of Acute Pediatric Leukemia

2021 ◽  
Vol 10 (16) ◽  
pp. 3556
Author(s):  
Jamie L. Stokke ◽  
Deepa Bhojwani
Keyword(s):  
De Novo ◽  
Lymphoblastic Leukemia ◽  
The United States ◽  
Cytotoxic Agents ◽  
Therapeutic Window ◽  
Acute Leukemias ◽  
Pediatric Leukemia ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

The clinical development of antibody–drug conjugates (ADCs) has gained momentum in recent years and these agents are gradually moving into frontline regimens for pediatric acute leukemias. ADCs consist of a monoclonal antibody attached to a cytotoxic payload by a cleavable linker. This structure allows for highly cytotoxic agents to be directly delivered to leukemia cells leading to cell death and avoids excessive off-tumor toxicity. Near universal expression on B-cell acute lymphoblastic leukemia (ALL) blasts and the ability of rapid internalization has rendered CD22 an ideal target for ADC in B-ALL. Inotuzumab ozogamicin, the anti-CD22 antibody linked to calicheamicin led to complete remission rates of 60–80% in patients with relapsed/refractory B-ALL. In acute myeloid leukemia (AML), the CD33 targeting gemtuzumab ozogamicin has demonstrated modest improvements in survival and is the only ADC currently licensed in the United States for pediatric patients with de novo AML. Several other ADCs have been developed and tested clinically for leukemia but have achieved limited success to date. The search for additional leukemia-specific targets and optimization of ADC structure and specificity are ongoing efforts to improve their therapeutic window. This review provides a comprehensive overview of ADCs in acute leukemias, with a focus on pediatric ALL and AML.

What Can We Learn about Antibody-Drug Conjugates from the T-DM1 Experience?

2015 ◽  
pp. e117-e125 ◽  
Author(s):  
Francisco J. Esteva ◽  
Kathy D. Miller ◽  
Beverly A. Teicher
Keyword(s):  
Small Molecule ◽  
Antibody Fragment ◽  
Cytotoxic Agents ◽  
Specific Cell ◽  
Malignant Cells ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Protein Toxin ◽  
Antibody Conjugates ◽  
Antibody Drug

Antibody conjugates are a diverse class of therapeutics that consist of a cytotoxic agent linked covalently to an antibody or antibody fragment directed toward a specific cell surface target expressed by tumor cells. The notion that antibodies directed toward targets on the surface of malignant cells could be used for drug delivery is not new. The history of antibody conjugates has been marked by hurdles identified and overcome. Early conjugates used mouse antibodies, drugs that either were not sufficiently potent, were immunogenic (proteins), or were too toxic, and linkers that were not sufficiently stable in circulation. Four main avenues have been explored using antibodies to target cytotoxic agents to malignant cells: antibody-protein toxin (or antibody fragment–protein toxin fusion) conjugates, antibody-chelated radionuclide conjugates, antibody-small molecule conjugates, and antibody-enzyme conjugates administered along with small molecule prodrugs that require metabolism by the conjugated enzyme to release the activated species. Technology is continuing to evolve regarding the protein and small molecule components, and it is likely that single chemical entities soon will be the norm for antibody-drug conjugates. Only antibody-radionuclide conjugates and antibody-drug conjugates have reached the regulatory approval stage, and there are more than 40 antibody conjugates in clinical trials. The time may have come for this technology to become a major contributor to improving treatment for patients with cancer.

Antibody-drug conjugates: Principles and clinical results in breast cancer treatment

2018 ◽  
Vol 39 (4) ◽  
pp. 490-495
Author(s):  
Nguyen Phuong Loan ◽  
Duong Hong Quan
Keyword(s):  
Breast Cancer ◽  
Cancer Treatment ◽  
Safety Data ◽  
Clinical Results ◽  
Breast Cancer Treatment ◽  
Surface Proteins ◽  
Cytotoxic Agents ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

Antibody-drug conjugates (ADCs) are consisted of the combination of highly specific monoclonal antibodies (mAbs) with conventional cytotoxic agents to particular cancer types. The use of mAbs that are specific to tumor cell-surface proteins allows highly selective accumulation of cytotoxic agents as ADCs at the tumor tissue, that is not achievable with conventional cytotoxic agents alone. Designing of effective ADCs for cancer treatment requires identification of an appropriate target, a mAb against the target, potent cytotoxic agents and conjugation of the mAb to cytotoxic agents. Until now, three ADCs including Gemtuzumab ozogamicin, Brentuximab and trastuzumab emtansine have received an FDA approval so far. These three ADCs have shown improved efficacy and safety data compared with standard chemotherapy for the treatment of patients of acute myeloid leukemia, advanced lymphoma and breast cancer, respectively. Moreover, several promising ADCs are now in the latter-phase of clinical testing. Thus, with special focusing on these new anti-cancer drugs, this review briefly describes the principles of ADCs including their structure and mechanism of action, and summarizes their clinical performance in breast cancer. Citation: Nguyen Phuong Loan, Duong Hong Quan, 2017. Antibody-drug conjugates: Principles and clinical results in breast cancer treatment. Tap chi Sinh hoc, 39(4): 489-493. DOI: 10.15625/0866-7160/v39n4.9327.*Corresponding author: [email protected] 15 March 2017, accepted 12 December 2017

scholarly journals Antibody-Drug Conjugates: A Promising Novel Therapy for the Treatment of Ovarian Cancer

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2223
Author(s):  
Aranzazu Manzano ◽  
Alberto Ocaña
Keyword(s):  
Ovarian Cancer ◽  
Therapeutic Strategy ◽  
Membrane Surface ◽  
Chemotherapeutic Agents ◽  
Novel Therapy ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Specific Antigens ◽  
Early Phase Clinical Trials ◽  
Antibody Drug

Antibody-drug conjugates (ADCs) represent a novel and promising therapeutic strategy for the treatment of cancer patients. ADCs target antigens highly expressed on the membrane surface of tumor cells to selectively deliver a cytotoxic drug. Ovarian tumors differentially express tumor-specific antigens, which can be used to guide ADCs. This strategy allows for optimizing tumor targeting while minimizing systemic toxicity compared to classical chemotherapeutic agents. ADCs can be improved by using a cleavable linker allowing the delivery of the toxic payload in surrounding cells not expressing the target protein, therefore acting on heterogeneous tumors with different cell populations. Currently, more than 15 ADCs are under preclinical investigation in ovarian cancer, and some of them have already been tested in early-phase clinical trials with promising results. In this review, we summarize the mechanism of action and the toxicity profile of ADCs and discuss the latest preclinical discoveries and forthcoming applications in ovarian cancer.

scholarly journals The Evolution of Antibody-Drug Conjugates: A Positive Inflexion Point

2020 ◽  
pp. 127-134 ◽  
Author(s):  
Anthony W. Tolcher
Keyword(s):  
Breast Cancer ◽  
B Cell Lymphoma ◽  
Cytotoxic Chemotherapy ◽  
Cytotoxic Agents ◽  
Full Potential ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Her2 Breast Cancer ◽  
The Many ◽  
Antibody Drug

In 2019, an important inflection point occurred when the U.S. Food and Drug Administration approved three new antibody-drug conjugates (ADCs) for the treatment of malignancies, including urothelial cancer (enfortumab vedotin-ejfv), diffuse large B-cell lymphoma (polatuzumab vedotin-piiq), and HER2 breast cancer (fam-trastuzumab deruxtecan-nxki), and expanded the indication for ado-trastuzumab emtansine to early breast cancer. This near doubling in the number of approved ADCs within 1 year validates the ADC platform and represents a successful evolution over the past 30 years. ADCs were born in an era when systemic therapy for cancer was largely cytotoxic chemotherapy. Many of the investigational cytotoxic agents were determined to be too toxic for oral and intravenous use. The agents were especially potent, with inhibitory concentrations that inhibited 50% of cells in the nanomolar and picomolar range but had poor therapeutic indexes when administered systemically. Now, over the last 30 years, we have seen an evolution of the many aspects of this complex platform with better antigen target selection, more sophisticated chemistry for the linkers, a growing diversity of payloads from cytotoxic chemotherapy to targeted therapies and immunostimulants, and, with the recent series of regulatory approvals, a buoyed sense of optimism for the technology. Nonetheless, we have not fully realized the full potential of this platform. In this review, the many components of ADCs will be discussed, the difficulties encountered will be highlighted, the innovative strategies that are being used to improve them will be assessed, and the direction that the field is going will be considered.

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