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 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.

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 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 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.

scholarly journals Breast Cancer Treatment and Antibody Drug Conjugates: Beyond T-DM1

2021 ◽  
Vol 9 (8) ◽  
Author(s):  
Mony Ung ◽  
Jean Lacaze ◽  
Eleonora Maio ◽  
Florence Dalenc
Keyword(s):  
Breast Cancer ◽  
Anticancer Agents ◽  
Bystander Effect ◽  
Cytotoxic Agents ◽  
Clinical Activity ◽  
Trastuzumab Emtansine ◽  
Her2 Positive ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

Antibody–drug conjugates (ADCs) are a new class of anticancer agents that combine cytotoxic agents attached by a linker to a monoclonal antibody. These engineered drugs can selectively deliver a cytotoxic payload to targeted cancer cells and the local microenvironment (bystander effect), thereby increasing activity and reducing off-target toxicity. The association of ADCs with other anti-cancer therapies is therefore promising. Trastuzumab-emtansine was the first approved ADC in breast cancer (BC), specifically for the management of human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer. New ADCs are in development in BC. Some have shown meaningful clinical benefit and have been recently approved, such as trastuzumab deruxtecan in HER2-positive trastuzumab emtansine (T-DM1) pretreated BC and Trop-2 guided sacituzumab govitecan in triple-negative BC. Trastuzumab deruxtecan also has potential clinical activity in HER2-low BC thanks to a bystander effect. In this article, we review the ADCs under development in advanced BC.

scholarly journals Hydrophilic Monomethyl Auristatin E Derivatives as Novel Candidates for the Design of Antibody-Drug Conjugates

Separations ◽  
2018 ◽  
Vol 6 (1) ◽  
pp. 1 ◽  
Author(s):  
Filip Ekholm ◽  
Suvi-Katriina Ruokonen ◽  
Marina Redón ◽  
Virve Pitkänen ◽  
Anja Vilkman ◽  
...  
Keyword(s):  
Micellar Electrokinetic Chromatography ◽  
State Of The Art ◽  
Cytotoxic Agents ◽  
Antibody Drug Conjugates ◽  
Hydrophilic Modification ◽  
Drug Conjugates ◽  
Selective Targeting ◽  
Free Molecules ◽  
Current Clinical Trial ◽  
Antibody Drug

Antibody-drug conjugates (ADCs) are promising state-of-the-art biopharmaceutical drugs for selective drug-delivery applications and the treatment of diseases such as cancer. The idea behind the ADC technology is remarkable as it combines the highly selective targeting capacity of monoclonal antibodies with the cancer-killing ability of potent cytotoxic agents. The continuous development of improved ADCs requires systematic studies on the nature and effects of warhead modification. Recently, we focused on the hydrophilic modification of monomethyl auristatin E (MMAE), the most widely used cytotoxic agent in current clinical trial ADCs. Herein, we report on the use of micellar electrokinetic chromatography (MEKC) for studying the hydrophobic character of modified MMAE derivatives. Our data reveal a connection between the hydrophobicity of the modified warheads as free molecules and their cytotoxic activity. In addition, MMAE-trastuzumab ADCs were constructed and evaluated in preliminary cytotoxic assays.

scholarly journals Treating Prostate Cancer by Antibody–Drug Conjugates

2021 ◽  
Vol 22 (4) ◽  
pp. 1551
Author(s):  
Matteo Rosellini ◽  
Matteo Santoni ◽  
Veronica Mollica ◽  
Alessandro Rizzo ◽  
Alessia Cimadamore ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Parp Inhibitors ◽  
Cytotoxic Agents ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Male Population ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Castration Resistant ◽  
Antibody Drug

Prostate cancer is the most frequent malignancy in the worldwide male population; it is also one of the most common among all the leading cancer-related death causes. In the last two decades, the therapeutic scenario of metastatic castration-resistant prostate cancer has been enriched by the use of chemotherapy and androgen receptor signaling inhibitors (ARSI) and, more recently, by immunotherapy and poly(ADP–ribose) polymerase (PARP) inhibitors. At the same time, several trials have shown the survival benefits related to the administration of novel ARSIs among patients with non-castration-resistant metastatic disease along with nonmetastatic castration-resistant cancer too. Consequently, the therapeutic course of this malignancy has been radically expanded, ensuring survival benefits never seen before. Among the more recently emerging agents, the so-called “antibody–drug conjugates” (ADCs) are noteworthy because of their clinical practice changing outcomes obtained in the management of other malignancies (including breast cancer). The ADCs are novel compounds consisting of cytotoxic agents (also known as the payload) linked to specific antibodies able to recognize antigens expressed over cancer cells’ surfaces. As for prostate cancer, researchers are focusing on STEAP1, TROP2, PSMA, CD46 and B7-H3 as optimal antigens which may be targeted by ADCs. In this paper, we review the pivotal trials that have currently changed the therapeutic approach to prostate cancer, both in the nonmetastatic castration-resistant and metastatic settings. Therefore, we focus on recently published and ongoing trials designed to investigate the clinical activity of ADCs against prostate malignancy, characterizing these agents. Lastly, we briefly discuss some ADCs-related issues with corresponding strategies to overwhelm them, along with future perspectives for these promising novel compounds.

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