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.

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 N-terminal selective conjugation method widens the therapeutic window of antibody–drug conjugates by improving tolerability and stability

mAbs ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 1914885
Author(s):  
Min Ji Ko ◽  
Daehae Song ◽  
Juhee Kim ◽  
Jae Yong Kim ◽  
Jaehyun Eom ◽  
...  
Keyword(s):  
Therapeutic Window ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Conjugation Method ◽  
Antibody Drug

Antibody-Drug-Conjugates for Breast Cancer

2021 ◽  
Author(s):  
Frederik Marmé
Keyword(s):  
Breast Cancer ◽  
Bystander Effect ◽  
Systemic Exposure ◽  
Clinical Development ◽  
Therapeutic Window ◽  
Target Cells ◽  
Magic Bullet ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

Background Despite the advances that have been made to improve conventional chemotherapies, their use is limited by a narrow therapeutic window based on off-target toxicities. Antibody-drug-conjugates (ADCs) are composed of an antibody and a toxic payload covalently coupled by a chemical linker. They constitute an elegant means to tackle the limitations of conventional chemotherapeutics by selectively delivering a highly toxic payload directly to target cells and thereby increasing efficacy of the delivered cytotoxic but at the same time limiting systemic exposure and toxicities. As such they appear inspired by Paul Ehrlich´s concept of a “magic bullet”, which he envisioned as drugs that go directly to their target to attack pathogens but remain harmless in healthy tissues. Summary The concept of conjugating drugs to antibodies via chemical linkers is not new. As early as in the 1960s researchers started to investigate such ADCs in animal models and first clinical trials based on mouse antibodies began in the 1980s. Although the concept appears relatively straightforward, ADCs are highly complex molecules, and it took several decades of research and development until the first ADC became approved by the FDA in 2000 and the second followed not until 11 years later. The development of an effective ADC is highly demanding, and each individual component of an ADC must be optimized: the target, the antibody, the linker and its conjugation chemistry as well as the cytotoxic payload. Today there are 9 approved ADCs overall and 3 for breast cancer. So, the pace of development seems to pick up with over 100 candidates in various stages of clinical development. Many ADCs of the newest generation are optimized to elicit a so-called bystander effect, to increase efficacy and tackle heterogneous antigen expression. This approach requires a balancing of efficacy and systemic toxicity. Hence, ADCs based on their complex biology cause relevant toxicities, which are characteristic for each specific compound and may include hematologic toxicities, elevated transaminases, gastrointestinal events, pneumonitis but also ocular toxicities as well as others many physicians may initially not be very familiar with. Management of the side effects will be key to the successful clinical use of these potent drugs. Key Messages This review focusses on the clinical experience with ADCs approved in breast cancer as well as promising candidates in late-stage clinical development. We will discuss the mode of action, biology, and composition of ADCs and how each of these crucial components influences their properties and efficacy.

Picking the Optimal Target for Antibody-Drug Conjugates

2013 ◽  
pp. e103-e107
Author(s):  
Rohan Mathur ◽  
George J. Weiner
Keyword(s):  
Critical Parameter ◽  
Therapeutic Agent ◽  
Therapeutic Window ◽  
Chemotherapeutic Drugs ◽  
Toxicity Profile ◽  
Cytotoxic Potential ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Optimal Target ◽  
Antibody Drug

Antibody-drug conjugates (ADCs) combine the cytotoxic potential of chemotherapeutic drugs with the specificity of monoclonal antibodies (mAbs). After many years of unfulfilled promise, the field of ADCs is experiencing resurgence as more is learned about each of the components of an ADC and how these components need to be combined to produce a successful therapeutic agent. Choosing an appropriate target for ADCs is a critical parameter that effects the efficacy, therapeutic window, and toxicity profile of ADCs. This review will focus on the concepts underlying the choice of the target, review specific current ADCs and their targets, and look to the future of ADCs.

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.

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.

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.

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