scholarly journals Bispecific Antibodies and Antibody–Drug Conjugates for Cancer Therapy: Technological Considerations

Biomolecules ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 360 ◽  
Author(s):  
Hyunbo Shim
Keyword(s):  
Therapeutic Antibody ◽  
Bispecific Antibodies ◽  
Target Antigen ◽  
Antibody Drug Conjugates ◽  
Medical Needs ◽  
Drug Conjugates ◽  
Recent Developments ◽  
Technological Developments ◽  
Approved Drugs ◽  
Antibody Drug

The ability of monoclonal antibodies to specifically bind a target antigen and neutralize or stimulate its activity is the basis for the rapid growth and development of the therapeutic antibody field. In recent years, traditional immunoglobulin antibodies have been further engineered for better efficacy and safety, and technological developments in the field enabled the design and production of engineered antibodies capable of mediating therapeutic functions hitherto unattainable by conventional antibody formats. Representative of this newer generation of therapeutic antibody formats are bispecific antibodies and antibody–drug conjugates, each with several approved drugs and dozens more in the clinical development phase. In this review, the technological principles and challenges of bispecific antibodies and antibody–drug conjugates are discussed, with emphasis on clinically validated formats but also including recent developments in the fields, many of which are expected to significantly augment the current therapeutic arsenal against cancer and other diseases with unmet medical needs.

Monoclonal Antibodies, Bispecific Antibodies and Antibody-Drug Conjugates in Oncohematology

2020 ◽  
Vol 15 (4) ◽  
pp. 272-292
Author(s):  
Romeo G. Mihăilă
Keyword(s):  
Monoclonal Antibodies ◽  
Target Cell ◽  
Residual Disease ◽  
Standard Of Care ◽  
Bispecific Antibodies ◽  
Target Antigen ◽  
Target Cells ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

Background: The therapeutic outcomes and the prognosis of patients with various hematologic malignancies are not always ideal with the current standard of care. Objective: The aim of this study is to analyze the results of the use of monoclonal antibodies, bispecific antibodies and antibody-drug conjugates for the therapy of malignant hemopathies. Methods: A mini-review was achieved using the articles published in Web of Science and PubMed between January 2017 and January 2020 and the new patents were made in this field. Results: Naked monoclonal antibodies have improved the therapeutic results obtained with standard of care, but they also have side effects and the use of some of them can lead to the loss of the target antigen through trogocytosis, which explains the resistance that occurs during therapy. The results obtained with naked monoclonal antibodies have been improved by a better monoclonal antibody preparation, the use of bispecific antibodies (against two antigens on the target cell surface or by binding both surface antigen on target cells and T-cell receptor complex, followed by cytotoxic T-lymphocytes activation and subsequent cytolysis of the target cell), the use of monoclonal or bispecific constructs in frontline regimens, combining immunotherapy with chemotherapy, including through the use of antibody-drug conjugates (which provides a targeted release of a chemotherapeutic agent). Conclusion: Immunotherapy and immuno-chemotherapy have improved the outcome of the patients with malignant hemopathies through a targeted, personalized therapy, with reduced systemic toxicity, which in some cases can even induce deep complete remissions, including minimal residual disease negativity.

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 Antibody-Drug Conjugates Designed to Eradicate Tumors with Homogeneous and Heterogeneous Expression of the Target Antigen

2006 ◽  
Vol 66 (6) ◽  
pp. 3214-3221 ◽  
Author(s):  
Yelena V. Kovtun ◽  
Charlene A. Audette ◽  
Yumei Ye ◽  
Hongsheng Xie ◽  
Mary F. Ruberti ◽  
...  
Keyword(s):  
Target Antigen ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Heterogeneous Expression ◽  
Antibody Drug

scholarly journals Antibody-Drug Conjugates and Targeted Treatment Strategies for Hepatocellular Carcinoma: A Drug-Delivery Perspective

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2861
Author(s):  
David Dahlgren ◽  
Hans Lennernäs
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Delivery ◽  
Cancer Cell ◽  
Cancer Biology ◽  
Cytotoxic Drug ◽  
Target Antigen ◽  
Target Cells ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

Increased understanding of cancer biology, pharmacology and drug delivery has provided a new framework for drug discovery and product development that relies on the unique expression of specific macromolecules (i.e., antigens) on the surface of tumour cells. This has enabled the development of anti-cancer treatments that combine the selectivity of antibodies with the efficacy of highly potent chemotherapeutic small molecules, called antibody-drug conjugates (ADCs). ADCs are composed of a cytotoxic drug covalently linked to an antibody which then selectively binds to a highly expressed antigen on a cancer cell; the conjugate is then internalized by the cell where it releases the potent cytotoxic drug and efficiently kills the tumour cell. There are, however, many challenges in the development of ADCs, mainly around optimizing the therapeutic/safety benefits. These challenges are discussed in this review; they include issues with the plasma stability and half-life of the ADC, its transport from blood into and distribution throughout the tumour compartment, cancer cell antigen expression and the ADC binding affinity to the target antigen, the cell internalization process, cleaving of the cytotoxic drug from the ADC, and the cytotoxic effect of the drug on the target cells. Finally, we present a summary of some of the experimental ADC strategies used in the treatment of hepatocellular carcinoma, from the recent literature.

scholarly journals Antibody-Drug Conjugates: The New Frontier of Chemotherapy

2020 ◽  
Vol 21 (15) ◽  
pp. 5510 ◽  
Author(s):  
Sara Ponziani ◽  
Giulia Di Vittorio ◽  
Giuseppina Pitari ◽  
Anna Maria Cimini ◽  
Matteo Ardini ◽  
...  
Keyword(s):  
First Generation ◽  
Antitumor Agents ◽  
Therapeutic Index ◽  
European Medicines Agency ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Recent Developments ◽  
Random Coupling ◽  
Personalized Cancer ◽  
Antibody Drug

In recent years, antibody-drug conjugates (ADCs) have become promising antitumor agents to be used as one of the tools in personalized cancer medicine. ADCs are comprised of a drug with cytotoxic activity cross-linked to a monoclonal antibody, targeting antigens expressed at higher levels on tumor cells than on normal cells. By providing a selective targeting mechanism for cytotoxic drugs, ADCs improve the therapeutic index in clinical practice. In this review, the chemistry of ADC linker conjugation together with strategies adopted to improve antibody tolerability (by reducing antigenicity) are examined, with particular attention to ADCs approved by the regulatory agencies (the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA)) for treating cancer patients. Recent developments in engineering Immunoglobulin (Ig) genes and antibody humanization have greatly reduced some of the problems of the first generation of ADCs, beset by problems, such as random coupling of the payload and immunogenicity of the antibody. ADC development and clinical use is a fast, evolving area, and will likely prove an important modality for the treatment of cancer in the near future.

Bispecific Antibodies and Antibody–Drug Conjugates (ADCs) Bridging HER2 and Prolactin Receptor Improve Efficacy of HER2 ADCs

2017 ◽  
Vol 16 (4) ◽  
pp. 681-693 ◽  
Author(s):  
Julian Andreev ◽  
Nithya Thambi ◽  
Andres E. Perez Bay ◽  
Frank Delfino ◽  
Joel Martin ◽  
...  
Keyword(s):  
Prolactin Receptor ◽  
Bispecific Antibodies ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

scholarly journals Antibody-Drug Conjugates: Patient and Treatment Selection

2020 ◽  
pp. 105-114
Author(s):  
Shalini Makawita ◽  
Funda Meric-Bernstam
Keyword(s):  
Patient Selection ◽  
Therapeutic Efficacy ◽  
Antigen Expression ◽  
Therapeutic Modality ◽  
Intratumor Heterogeneity ◽  
Target Antigen ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
The Impact ◽  
Antibody Drug

Antibody-drug conjugates (ADCs) are a promising drug platform designed to enhance the therapeutic index and minimize the toxicity of anticancer agents. ADCs have experienced substantial progress and technological growth over the past decades; however, several challenges to patient selection and treatment remain. Methods to optimally capture all patients who may benefit from a particular ADC are still largely unknown. Although target antigen expression remains a biomarker for patient selection, the impact of intratumor heterogeneity on antigen expression, as well as the dynamic changes in expression with treatment and disease progression, are important considerations in patient selection. Better understanding of these factors, as well as minimum levels of target antigen expression required to achieve therapeutic efficacy, will enable further optimization of selection strategies. Other important considerations include understanding mechanisms of primary and acquired resistance to ADCs. Ongoing efforts in the design of its constituent parts to possess the intrinsic ability to overcome these mechanisms, including use of the “bystander effect” to enhance efficacy in heterogeneous or low target antigen-expressing tumors, as well as modulation of the chemical and immunophenotypic properties of antibodies and linker molecules to improve payload sensitivity and therapeutic efficacy, are under way. These strategies may also lead to improved safety profiles. Similarly, combination strategies using ADCs with other cytotoxic or immunomodulatory agents are also under development. Great strides have been made in ADC technology. With further refinements, this therapeutic modality has the potential to make an important clinical impact on a wider range of tumor types.

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