The Pharmacology Of Antibody-Drug Conjugates: Chemistry, Mechanism Of Action, And Advantages/Disadvantages

The pharmacology of antibody-drug conjugates.

Include in your analysis details of chemistry, toxicity, efficacy, mechanism of action, use for particular cancers, clinical need, specificity for target, and advantages / disadvantages.

Introduction to Antibody-Drug Conjugates

Antibody-drug conjugates (ADC) are the monoclonal antibodies that attached to the drugs that are biologically active by linkers with the help of labile bonds. By combining, the specific targeting of monoclonal antibodies with the cytotoxic drug that has the ability to kill cancer cells, ADCs allow the discrimination between the health and diseased group of cells (Lonza, 2018). Over the past 50 years, the cancer management is improved with a lot of advancement in chemotherapy, which becomes a major cancer treatment when with cytotoxic agents. With some improvement in ADC technology more effective results can be achieved (Tsuchikama and An, 2018). The chemistry of conjugation and linkers, efficacy, mechanism of action of antibody-drug conjugates, application of ADCs in various types of cancer, target specificity, clinical need, advantages and disadvantages of ADC will be discussed in this report.  

Linkers play an important role to stabilize the ADC to the tumour cells. The needs to possess some key attributes such as its stability in plasma after the drug administered for a long time so that the ADC can bind to tumour cells. The stability of linkers ensures the prevention of premature release of a cytotoxic payload, which would damage all kind of cells and lower the therapeutic effects of ADC. Linkers also have the ability to possess effect on ADCs physicochemical properties (Alley, Okeley, and Senter, 2010).

The chemistries of conjugation and a linker are the crucial components to a successful construction of the ADCs. A Linkers Moiety attached to the antibody with by covalent bonds and payload the components. The molecular design and its properties are the crucial determinant factor for ADC. Linkers need to possess stability in plasma to construct ADC successfully, needs to release the toxic payload, and needs to possess hydrophobicity. The hydrophobic linkers promote the aggregation of ADC. In the ADC chemical conjugation, the amino acids residues undergo a reaction with the reaction handle on a linker. The process includes a mixture of the ADC molecules with DARs (Drug- antibodies Ratios) and the tethering sites. The high DAR is able to increase the toxic payload in circulation. Some of the conjugation methods are lysine amide coupling, cysteine coupling and incorporation of non-amino acid by genetic engineering (Tsuchikama and An, 2018).  

The major toxicity of Antibody-drug conjugates includes hepatic, hematologic, neurologic, and ophthalmic reactions. These issues can be raised due to the off-target outcomes caused by a premature release of the payload in blood circulation. Some of the other toxicity events associated with ADC are thrombocytopenia, neutropenia, ocular toxicity, peripheral neuropathy, skin toxicity, toxicity to endothelial cells and gastrointestinal toxicity (Donaghy, 2016).

Chemistry of Linkers and Conjugation

The antibody-drug conjugation therapy is important to directly eliminate the cancer cells.it is a more advanced technology with fewer side effects. Use molecule such s folic acid and growth hormone can effectively increase the antitumor activity. A study conducted by Xiunhua et al. (2018) shows that Erbitux-VC-PAB-MMAE is able to effectively the proliferation of the A549 cells that are responsible for the development of human lung cancer. It arrests the cell cycle at the G2/M phase and effectively stops the tumour growth by promoting the apoptosis of the cell (Kang et al. 2018).  

ADCs are becoming the latest generation of the anti-cancer drugs and the important newest class of a highly potent biopharmaceutical. ADC provides a life-saving strategy to cure the patient with a tumour in a sustained manner. The highly hydrophobic payloads are problematic in the aggregation of ADCs. Effective aggregation control strategies and use of best payload need to be used to stop the failure of ADCs construction (The Pharma Letter, 2017).

A monoclonal antibody is specific to its target to release the cytotoxic drug.  The cytotoxic molecules are highly specific to antigens that are associated with tumour cells. Tumour-target antigen selection is the main parameter while developing an ADC (Kim and Kim, 2015).   

The ADC therapy is effective in various types of cancer. This technology provides a new therapeutic solution for cancer treatment and the effectiveness of this treatment requires the composed action of antibodies, a linker, and a cytotoxic payload. Antibody-drug conjugate such as AMG-172,Anti-CD22_MCC-DM1, BAY 94-9343, IMGN-529,IMGN853, lorvotuzumab,ASG-5ME, DCDT2980s, SGN, PF and ADCT-402 are specific for different type of cancer like ovarian cancer, NHL, solid tumours, pancreatic cancer, urothelial tumours, non-Hodgkin lymphoma haematological malignancies, RCC, breast cancer, B-cell malignancy, Prostate cancer, colorectal cancer, and renal carcinoma (Parslow et al. 2016).

A general structure of advanced drug conjugates contains the humanized monoclonal antibodies, a chemical linker, and the payload. A linker is attached to mAB by the covalent bond at conjugation site.

ADC's mechanism of action is a many step process that depends upon the type of linker and the drugs. The first step of the mechanism of antibody-drug conjugates includes the binding of antibody-part of an ADC to the antigen present on the cell surface. This results in the formation of the antigen-ADC complex, which is further internalized into the endosomes (Bouchard, Viskov and Garcia-Echeverria, 2014). Endosome acidification reduces the PH from 7.4 to nearly pH 5.5-6.0. Endosomes is then attached to lysosomes, where the pH is decreased to 5.0 to 5.5 triggering the lysosome proteases. Linkers are sensitive to pH and drop in pH leads to the cleaving of linkers and releasing the drug.  For example, a benzyl-carbonate linker in an anti-TROPPP2-CL2A-SN38 may conjugate IMMU-132, which can be hydrolysed at pH 5.0 to yield an SN-38. The function of lysosome required for the activity of disulphide, which contains ADC and the protease-sensitive linkers as a lysosome inhibitor. Inside a lysosome, an antibody of ADC catabolizes into molecules of amino acids to release the linker-drug. Maytansine-based linker catabolites such as lysine-MC-DM1 released from lysosomes via SLC46A3 that is a lysosomal transporter. For antibody-drug conjugates with the disulphide, linker lysine-SPDB-DM4 is formed. After that, the linker is cleaved to form a DM4 including a free sulfhydryl, which is further methylated to generate S-methyl- DM4. After the cleavage of the valine-citrine bond, the self-immolation of PABC (para-amino benzyloxy carbonyl) takes place to form MMAE (Monomethyl auristatin E). The release of the MMAE after the proteolytic- cleavage results in microtubule depolarisation and finally in cancer cell death (Flygare, Pillow, and Aristoff, 2013).

Toxicity of ADCs

Steps involved in the mechanism  

 ADC binds to the target antigen on the tumour cell surface to form ADC- antigen complex.

Internalization: the complex is then internalized through the receptor-mediated endocytosis

Degradation: degradation of ADC takes place inside lysosome to release a cytotoxic drug.

Release: the released drug is then entered cytoplasm and bind to the molecular target

Cell death: apoptosis of a cell occurs after the drugs interact with the DNA or microtubule of the cell (ResearchGate, 2018).

Advantages 

The main advantage of using ADC for cancer therapy is that it has targeted therapeutic attachment or binding to a specific target antigen. It also transports highly potent agents that are selective to the tumour cells. The antibody-drug conjugates have with therapeutic index. The conjugate of antibody drug can remain stable in the bloodstream because ADCs has prolonged circulation half-life. Almost all the anticancer therapies have side effects but ADC therapy has decreased adverse effects. ADC combines mABs that have targeting ability with cytotoxic drugs. ADCs are highly specific to their target receptor. ADCs have less off-target action than other therapeutic cytotoxic molecules. The high specificity of ADC and its controllable mechanism make sure that more drugs bind to the target. This means that the there is less concentration is required to exhibit the therapeutic response than other small molecule co-therapy (Janthur, Cantoni and Mamot, 2012).  

The ADCs are effective for a limited time.in relation to exhibiting the response, ADC must target the extracellular receptor. These extracellular targets sometimes not found on the cell and it might be toxic to another cell that also has the target receptor. The ADC conjugates are large size conjugate (nearly 150kD) which makes it penetrate solid tumours (mAbstalk, 2015).  Tumours need to be examined in case ADC for the expression of antigen. The targeted molecule sometimes has normal tissues expression, which can lead to toxicity. The toxic payloads may result in premature release. The conjugates of antibodies may not bind to target cells in enough concentration to be lethal. The expression of antigens can be heterogeneous in case of a solid tumour (Teicher, 2014).  

Conclusion

The antibody-drug conjugates or ADCs are the monoclonal antibodies that bind to the biological active drugs with the help of linker by labile bonds. The chemistries of conjugation and linker hare place an important part to construct ADC. The hydrophobic linker helps to aggregate the ADCs. The ADCs also have toxicity such as hepatic neurologic and ophthalmic events that can be occurred due to the premature release of payloads in the bloodstream. The ADC therapy has efficacy to eliminate the infected cells directly by arresting the G2/M phase. This therapy can be useful in various types of cancer such as ovarian cancer, pancreatic cancer, breast cancer, prostate cancer, renal carcinoma and colorectal cancer. The ADC mechanism takes place in various steps like binding, internalization, degradation of ADC to release drug, release and finally cell death. ADC therapy has various advantages such its specificity to the targets and transportation of highly potent agent. However, it also has some disadvantages like its large size but the more advancement in this technology may diminish the disadvantages in coming future.

References

Alley, S.C., Okeley, N.M. and Senter, P.D. (2010) Antibody-drug conjugates: targeted drug delivery for cancer. Current opinion in chemical biology, 14(4), pp.529-537.

Bouchard, H., Viskov, C., and Garcia-Echeverria, C. (2014) Antibody-drug conjugates—a new wave of cancer drugs. Bioorganic & medicinal chemistry letters, 24(23), pp.5357-5363.

Chen, H., Lin, Z., Arnst, K. E., Miller, D. D., and Li, W. (2017) tubulin inhibitor-based antibody-drug conjugates for cancer therapy, Molecules, 22(8), p. 1281.

Donaghy, H. (2016) Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody-drug conjugates. Taylor & Francis, 8(4), pp. 659-671.

Flygare, J.A., Pillow, T.H. and Aristoff, P. (2013) Antibody?drug conjugates for the treatment of cancer. Chemical biology & drug design, 81(1), pp.113-121.

Janthur, W.D., Cantoni, N. and Mamot, C. (2012) Drug conjugates such as antibody-drug conjugates (ADCs), immunotoxins and immunoliposomes challenge the daily clinical practice. International journal of molecular sciences, 13(12), pp.16020-16045.

Kang, X., Zhou, L., Jian, Y.M., Lan, S.A. and Xu, F. (2018) Effectiveness of Antibody-Drug Conjugate (ADC): Results of In Vitro and In Vivo Studies. Medical science monitor: international medical journal of experimental and clinical research, 24, p.1408.

Kim, E.G. and Kim, K.M. (2015) Strategies and advancement in antibody-drug conjugate optimization for targeted cancer therapeutics. Biomolecules & Therapeutics, 23(6), p.493.

Lonza (2018) Antibody Drugs conjugates (ADCs) [online]. Available from: https://www.lonza.com/custom-manufacturing/small-molecule-technologies/antibody-drug-conjugates-adcs.aspx [Accessed 29 June 2018].

mAbstalk (2015) ADCs: Pros and cons [online]. Available from: https://mabstalk.com/2015/01/27/adcs-pros-and-cons/ [Accessed 30 June 2018].

Parslow, A.C., Parakh, S., Lee, F.T., Gan, H.K. and Scott, A.M. (2016) Antibody-drug conjugates for cancer therapy. Biomedicines, 4(3), p.14.

ResearchGate (2018) Structure and mechanism of action of ADC [online]. Available from: https://www.researchgate.net/figure/Structure-and-mechanism-of-action-of-ADC-A-A-general-structure-of-an-ADC-containing-a_fig7_309141197 [Accessed 30 June 2018].

Teicher, B. A. (2014) antibody-drug conjugates. Current opinion in oncology, 26(5), pp. 476-483.

The Pharma Letter (2017) the imperative need for aggregation solutions to prevent best in class ADC targets failing and facing long delays in clinical development [online]. Available from: https://www.thepharmaletter.com/article/the-imperative-need-for-aggregation-solutions-to-prevent-best-in-class-adc-targets-failing-and-facing-long-delays-in-clinical-development [Accessed 30 June 2018].

Tsuchikama, K. and An, Z. (2016) Antibody-drug conjugates: recent advances in conjugation and linker chemistries. Protein & cell, 9(1), pp.1-14.