Antibody structure and engineering considerations for the design and function of Antibody Drug Conjugates (ADCs) (original) (raw)
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Antibody-Drug Conjugates: The New Frontier of Chemotherapy
International Journal of Molecular Sciences
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 co...
Antibody-Drug Conjugates for Cancer Therapy: Chemistry to Clinical Implications
Pharmaceuticals (Basel, Switzerland), 2018
Chemotherapy is one of the major therapeutic options for cancer treatment. Chemotherapy is often associated with a low therapeutic window due to its poor specificity towards tumor cells/tissues. Antibody-drug conjugate (ADC) technology may provide a potentially new therapeutic solution for cancer treatment. ADC technology uses an antibody-mediated delivery of cytotoxic drugs to the tumors in a targeted manner, while sparing normal cells. Such a targeted approach can improve the tumor-to-normal tissue selectivity and specificity in chemotherapy. Considering its importance in cancer treatment, we aim to review recent efforts for the design and development of ADCs. ADCs are mainly composed of an antibody, a cytotoxic payload, and a linker, which can offer selectivity against tumors, anti-cancer activity, and stability in systemic circulation. Therefore, we have reviewed recent updates and principal considerations behind ADC designs, which are not only based on the identification of tar...
Antibody-drug conjugates (ADCs) have emerged as a promising class of anticancer agents, combining the specificity of antibodies for tumor targeting and the destructive potential of highly potent drugs as payload. An essential component of these immunoconjugates is a bifunctional linker capable of reacting with the antibody and the payload to assemble a functional entity. Linker design is fundamental, as it must provide high stability in the circulation to prevent premature drug release, but be capable of releasing the active drug inside the target cell upon receptor-mediated endocytosis. Although ADCs have demonstrated an increased therapeutic window, compared to conventional chemotherapy in recent clinical trials, therapeutic success rates are still far from optimal. To explore other regimes of half-life variation and drug conjugation stoichiometries, it is necessary to investigate additional binding proteins which offer access to a wide range of formats, all with molecularly defined drug conjugation. Here, we delineate recent progress with site-specific and biorthogonal conjugation chemistries, and discuss alternative, biophysically more stable protein scaffolds like Designed Ankyrin Repeat Proteins (DARPins), which may provide such additional engineering opportunities for drug conjugates with improved pharmacological performance.
Antibody drug conjugates: Progress, pitfalls, and promises
Human antibodies, 2018
Antibody drug conjugates (ADC's) represent a promising and an efficient strategy for targeted cancer therapy. Comprised of a monoclonal antibody, a cytotoxic drug, and a linker, ADC's offer tumor selectively, reduced toxicity, and improved stability in systemic circulation. Recent approvals of two ADC's have led to a resurgence in ADC research, with more than 60 ADC's under various stages of clinical development. The therapeutic success of future ADCs is dependent on adherence to key requirements of their design and careful selection of the target antigen on cancer cells. Here we review the main components in the design of antibody drug conjugates, improvements made, and lessons learned over two decades of research, as well as the future of third generation ADCs.
THE NEW AGE SAVIOUR FOR COMBATING CANCER: ANTIBODY DRUG CONJUGATES.
Traditional techniques opted to treat cancer were found to be extremely harmful to the tissues when given at a slightly higher dose. ADCs (Antibody Drug Conjugates) have transformed the field of cancer chemotherapy. ADCs use monoclonal antibodies (mAbs) to explicitly tie tumour-related target antigens and convey an exceptionally powerful cytotoxic agent. The synergistic mix of mAbs conjugated too little molecule chemotherapeutics, through a stable linker, has given rise to an adequate class of anti-cancer drugs with an effectively extensive and quickly developing clinical pipeline. Antibody drug conjugates (ADCs) are an important division of therapeutics that allows the antigen-selective ability of mAbs to deliver highly potent cytotoxic drugs at the site of antigen-expressing tumor cells. The utilization of mAb coordinated delivery can present a high therapeutic index to exceptionally strong cytotoxic drugs, expanding both the efficacy and level of safety of the treatment. In other words, to achieve the goal of highly improved therapeutic efficacy and reduced toxicity, each component of an ADC i.e. the mAb, linker and the drug needs to be considered in context of targeted antigen. Furthermore, the mechanism of ADCs, characteristics of targets, methods of preparation, linker drugs being used in ADC design and regulatory requirements for new drug approval are discussed.
Antibody drug conjugate: the “biological missile” for targeted cancer therapy
Signal Transduction and Targeted Therapy, 2022
Antibody–drug conjugate (ADC) is typically composed of a monoclonal antibody (mAbs) covalently attached to a cytotoxic drug via a chemical linker. It combines both the advantages of highly specific targeting ability and highly potent killing effect to achieve accurate and efficient elimination of cancer cells, which has become one of the hotspots for the research and development of anticancer drugs. Since the first ADC, Mylotarg® (gemtuzumab ozogamicin), was approved in 2000 by the US Food and Drug Administration (FDA), there have been 14 ADCs received market approval so far worldwide. Moreover, over 100 ADC candidates have been investigated in clinical stages at present. This kind of new anti-cancer drugs, known as “biological missiles”, is leading a new era of targeted cancer therapy. Herein, we conducted a review of the history and general mechanism of action of ADCs, and then briefly discussed the molecular aspects of key components of ADCs and the mechanisms by which these key ...
Antibody-drug conjugates in cancer therapy—filling in the potholes that lie ahead
Cancer
Antibody-Drug Conjugates, com-posed of a cytotoxic drug conjugated to a tumour cell targeting antibody are being extensively studied and tested for the treatment of a variety of cancers. Antibody-Drug Conjugate systems hold the promise of more selective drug therapy compared to traditional chemotherapy, with fewer side effects. These important advantages have stimulated excit-ing developments in various aspects of Antibody-Drug Conjugate tech-nology. Although several Antibody-Drug Conjugates have now entered the clinic, a number of biological and technical pitfalls exist that will need to be overcome if Antibody-Drug Conjugates are to fulfil their full therapeutic potential. This paper will discuss the more important of these challenges.
Modulation of drug-linker design to enhance in vivo potency of homogeneous antibody-drug conjugates
Journal of controlled release : official journal of the Controlled Release Society, 2017
Antibody-drug conjugates (ADCs) are a promising class of anticancer agents which have undergone substantial development over the past decade and are now achieving clinical success. The development of novel site-specific conjugation technologies enables the systematic study of architectural features within the antibody conjugated drug linker that may affect overall therapeutic indices. Here we describe the results of a systematic study investigating the impact of drug-linker design on the in vivo properties of a series of homogeneous ADCs with a conserved site of conjugation, a monodisperse drug loading, a lysosomal release functionality and monomethyl auristatin E as a cytotoxic payload. The ADCs, which differed only in the relative position of certain drug-linker elements within the reagent, were first evaluated in vitro using anti-proliferation assays and in vivo using mouse pharmacokinetics (PK). Regardless of the position of a discrete polymer unit, the ADCs showed comparable in...
Emerging Role of Antibody Drug Conjugates (ADCs) in Therapeutics: An Appraisal
2017
Antibody drug conjugates intends to pursue the monoclonal antibodies (mAbs) as the potent source of delivering cytotoxic drugs to more specific site which binds selectively to the antigen expressing tumor cells. Inspite of the facts, various other safety profile must be considered while designing and optimizing ADC such as selecting congruous target antigen and method of conjugation. Each and every component of the ADC i.e antibody, linker and the drug should be optimized to the extent of desirable targeted therapy which will ameliorate as well as enhance tolerability. The past decade had witnessed advances in newer cancer treatments with extremely selective small molecules targeting the specific genetic abnormality causing the disease. The approach of traditional cytotoxic agents in the treatment of cancer, unlike the target specificity, they affect both healthy as well as cancer cells. In order to build a powerful and more specific cytotoxic agent with target oriented mAb’s design...