Antibody Drug Conjugate
An Antibody Drug Conjugate (ADC) is a type of targeted cancer therapy that combines an antibody with a cytotoxic drug. The antibody specifically targets cancer cells, delivering the drug directly to the tumor cells while minimizing damage to healthy cells. This approach can enhance the effectiveness of chemotherapy and reduce side effects.
5 Key excerpts on "Antibody Drug Conjugate"
eBook - ePubTherapeutic Antibody Engineering
Current and Future Advances Driving the Strongest Growth Area in the Pharmaceutical Industry
- William R Strohl, Lila M Strohl(Authors)
- 2012(Publication Date)
- Woodhead Publishing(Publisher)
...15 Antibody-drug conjugates Abstract: Various methods have been used to improve the ability of antibodies to kill cells, perhaps the most complex of which are antibody-drug conjugates (ADCs). ADCs require an antibody or targeting moiety, a linker, and a toxic chemical. The antibody can be an IgG, an antibody fragment, or even a nonantibody binding protein. The linker is typically either a synthetic chemical linker or a peptide linker, and the toxic chemical can be either a cytotoxic natural product derivative such as monomethyl auristatin, a peptide or protein toxin usually derived from bacteria or plants, or a radionuclide. While in the past, ADCs were not significant drugs, recent improvements have made the newer generation of ADCs much more likely to succeed as therapeutics. Radionuclide-based conjugates also can be used for a variety of imaging modalities as diagnostics. Keywords antibody-drug conjugates (ADCs) chemical warheads (payload) linker natural products doxorubicin calicheamicin maytansanoids monomethyl auristatins duocarmycins bystander effect immunotoxins PE38 radioimmunoconjugates PET SPECT imaging 15.1 Introduction to antibody-drug conjugates Antibody-drug conjugates (ADCs) are defined as antibodies to which other molecules are bound through a chemical linker. The term “conjugate” differentiates these modified antibody forms from peptide fusions that may be genetically fused to N- or C-termini of either the light or heavy chains of the antibody. The general principle of ADCs is to use the antibody to target a particular cell population, thereby carrying the conjugated molecule to that targeted cell population so that it can exert most, if not all, of its pharmacological activity upon just that population...
eBook - ePub- Bhupinder Singh, Bhupinder Singh(Authors)
- 2018(Publication Date)
- CRC Press(Publisher)
...The antibody–drug conjugates (ADCs) are internalized by receptor-mediated endocytosis and remain inactive prior to any transformation into the body. Once internalized, the ADC gets converted into the active form releasing the anticancer drugs in the tumour cell environment. In case of ADCs, it is imperative to calculate the ratio of antibody to drug in an optimal manner so as to achieve maximal safety and efficacy (Schrama et al., 2006). Nevertheless, immunological consequences, tumour permeability and specific delivery are the raising concerns that need to be addressed prior to the fruitful clinical application. Deficiency of cell permeability is the foremost obstacle for ADCs (Stohrer et al., 2000), which can be achieved by employing fragments of antibodies like scFv and Fab and internalized more efficiently into cancerous cells as compared to the intact antibodies. Instances of recently used tumour-specific antigens include prostate membrane specific antigen (PSMA), TAG-72, αv integrin, CD19, CD22, MUC16 and epidermal growth factor receptor (EGFR). Expression of MUC16 is much more profound in ovarian cancer cells rather than tumours of different origins (Gires and Seliger, 2009). Likewise, the expression of PSMA is preferentially associated with prostate cancerous tissues (Wang et al., 2009). On the other hand, regardless of origin, some antigens show high degree of affinity to tumour cells, e.g. TAG-72 is preferentially associated in human adenocarcinomas, encompassing gastric, breast, colorectal, pancreatic, lung (non-small cell), endometrial and ovarian cancers. Several anticancer bioactives have also been modified and conjugated to tumour-specific antibodies. These includes, antifolates (Schrama et al., 2006), vinca alkaloids (Spearman et al., 1987), anthracyclines (Senter, 2009), taxanes (Quiles et al., 2010), monomethyl auristatin E (Senter, 2009), calichemicin (Boghaert et al., 2008) and mytansine derivative DM1 (Krop et al., 2010)...
eBook - ePub- Matzku(Author)
- 2019(Publication Date)
- CRC Press(Publisher)
...The concept of the “magic bullet” against cancer cells is a rational approach to targeted cancer therapy and has been introduced in the clinical setting by the application of antibody-drug and antibody-toxin conjugates. Although the original concept of targeted cytotoxicity has lost some of its attractiveness due to the limitations and disappointing clinical results achieved with solid tumors, it has demonstrated promising therapeutic potential in the treatment of hematopoietic malignancies, localized disease in areas not accessible for surgery, and in ex vivo purging studies. Recently, the idea to combine in a single moiety cell recognition and antitumor function has been applied in other areas of ligand-mediated targeting and is the rationale also for the retargeting of effector cells of the immune system. Based on the progress and advances made in molecular oncology and in the understanding of antibody and drug activity, the preparation of a new generation of antibody conjugates has been addressed by many investigators. It is now possible to produce tailor-made antibodies with improved tumor localization properties, and better or more linkage sites for hydrophobic drugs in quantities sufficient for human therapy. In addition, novel cytotoxic drugs of defined activity are available, and genetic engineering techniques and improvements in linker technology have allowed the conjugation of these missiles to antibodies. In the future, major improvements can be expected from developments in three areas. First, identification of truly tumor-specific antigens or of novel tumor-associated antigens which are more selectively expressed on tumor cells compared to normal tissues. Second, the generation of cytotoxic antibody conjugates with defined structure which display improved potency and selectivity, improved tumor localization, lower toxicity and reduced immunogenicity...
- Saghir Akhtar, Saghir Akhtar(Authors)
- 2017(Publication Date)
- CRC Press(Publisher)
...We are currently measuring the pharmacokinetics and biodistribution of such conjugates. IV. Conjugation Techniques and Choice of Linker Many diverse molecules have been conjugated to monoclonal antibodies with the ultimate aim of targeted therapy. These conjugates include a number of isotopes, cytotoxic agents, a range of plant, animal, or bacterial toxins, and more recently novel enzymes to activate prodrugs 19 or denature intracellular macromolecules such as DNA or RNA. 20 Several classes of cytotoxic drugs have been investigated tor the design of immunoconjugates including alkylating agents, antimetabolites, vinca alkaloids and their analogs, and, in particular, methotrexate. 4, 21 Linkage to the antibody is obtained through endogenous reactive groups such as amino, hydroxyl, carboxyl, or sulfydryl groups which are not required for drug action. Numerous chemical means have been described to couple toxins to antibodies. 22 A number of high-activity enzymes such as alkaline phosphatase and horse radish peroxidase have also been similarly conjugated for use in immunological assays. 23, 24 The earliest attempts made use of homobifunctional reagents such as glutaraldehyde, 25 toluene diisocyanate, 26 or diethyl malonimidate 27 that cross linked free amino groups found on both proteins. This often resulted in a number of undesirable side products such as homopolymers and large protein aggregates. The development of heterobifunctional cross linkers such as m -maleimidobenzoyl- N -hydroxysuccinimide ester (MBS), succinimidyl 4-(N -maleimidomethyl)cyclohexane-1carboxylate (SMCC), and N -succinimidyl-3-(2-pyridyldithio)propionate (SPDP) has permitted the highly specific cross linking of many proteins by introducing different chemical functionalities onto each protein molecule...
eBook - ePubMonoclonal Antibodies
The Second Generation
- Heddy Zola, Heddy Zola(Authors)
- 2020(Publication Date)
- Garland Science(Publisher)
...In view of the foregoing, highly toxic drugs and toxins, too toxic to use alone (e.g. aminopterin, calicheamycin, ricin), can be conjugated to monoclonal antibodies and used in vivo without toxicity (Hinman et al., 1990; Kanellos et al., 1988; Krauer et al., 1993). (6) In patients, more than 2 g of monoclonal antibody may usually be given without ill effects (unless specifically toxic on a tissue) (Gould et al., 1989; Tjandra et al., 1989). (7) Drugs conjugated to monoclonal antibody can be given at doses greater than the maximum tolerated dose of free drug (Tjandra et al., 1989). (8) The half-life of drug attached to antibody is greater than that of free drug. (9) Almost all patients make anti-mouse antibodies when given murine antibodies. (10) The uptake of murine monoclonal antibody into tumors is approximately 10–20% injected dose g -1 in animals and less than 1% in patients; it is therefore important to investigate methods to improve tumor access and to make more effective immunoconjugates. To this end, we have used tumor necrosis factor-α (TNF-α) and vasoactive agents in conjunction with immunoconjugates and showed improved antitumor effects in vivo (Russell et al., 1990; Smyth et al., 1987). Using recombinant antibody engineering techniques, it is possible to construct smaller antibody molecules that retain the binding characteristics of the parent antibody, and it is also possible to engineer antibodies that are less immunogenic in humans, so opening up a whole new era of making and modifying antibodies and fragments and genetically engineering toxin—antibody conjugates. This chapter will examine the current technology for constructing recombinant antibodies and their use in the construction of recombinant immunotoxins and other fusion proteins of diagnostic and therapeutic value. 3...
