ADCs

Background


BOC Sciences has directed sincere efforts toward providing customers with top quality products designed for optimum Antibody-drug Conjugates. Toxin with Linkers is the preponderant production we supply for customers.

Antibody-drug Conjugates or ADCs consist of an antibody, a cytotoxic drug, and a linker that attaches the two. Such conjugates exhibit a broadly applicable method to increase the antitumor activity of antibodies and improve the tumor-to-normal tissue selectivity of chemotherapy. An ideal ADC has a selective monoclonal antibody and a highly potent drug, mixed with properly stable linker systems and conjugation technologies that preserve the characteristics of the antibody. ADCs could theoretically be to target just about any biological tumor target as long as it can be reached by internalizing antibodies.

The monoclonal antibody binds to an antigen that is selectively expressed on the surface of a tumor cell. Upon binding, the antibody gets absorbed into the cell via receptormediated endocytosis and the antibody is trafficked to and degraded in the lysosome. This delivers the cytotoxic agent directly inside the targeted cancer cell. The choice of the cytotoxin and the exact nature of the connection to the antibody are critical for the success of this method.

There are 3 critical components of an ADC: the monoclonal antibody, the cytotoxic drug and the linker. Ideally, the the monoclonal antibody will specifically bind to an antigen with substantial expression on tumor cells but limited expression on normal tissues. And the linker should be stable in systemic circulation to allow delivery of the intact ADC to the targeted antigen presented on the surface of the tumor cell. Besides, the linker must then be labile enough to allow efficient release of the cytotoxic drug inside the targeted tumor cell. The cytotoxic drug bounds to the antibody needs to be highly potent so that the ADCs that do reach the target cell have the maximum killing potential.

ADCs background

Early work on ADCs relied on clinically approved chemotherapeutic drugs with the aim to increase tumor specificity. A prominent example of this first-generation ADCs is represented by BR96-doxorubicin. Doxorubicin was attached to a chimeric version of the BR96 antibody, through an acid-labile hydrazone linker. But clinical trials show that the limitations of BR96-doxorubicin include low molar potency of the cytotoxic drug and antigen expression on sensitive normal tissue. Further advancements, Mylotarg is the first ADC to gain FDA approval in 2000 but was withdrawn from the market a decade later owing to a lack of improvement in overall survival. And it took almost a decade before the next ADC was approved. Today ADCs are developed starting from mAbs that selectively bind to tumors and display little cross-reactivity with healthy tissues. Moreover, the appropriate mAb formatmay have to be selected in order to tune ADC tumor uptake and blood clearance properties with linker stability and drug release, thus minimizing the exposure of healthy organs to toxic agents.

From The Antibody Drug Conjugates Market (3rd edition), 2015-2025 report, the ADC market was worth approximately USD 900 million in 2015 with just two approved drugs. Significant advances have been made with ADCs over the last 3 decades. In the future, some researchers envisage that novel linkers chemistry (including traceless linkers) and non-internalizing antibodies will expand the repertoire of tools for ADC development.

Reference:
Antibody–drug conjugates: targeted drug delivery for cancer. Stephen C Alley, Nicole M Okeley and Peter D Senter. Current Opinion in Chemical Biology 2010, 14:529–537
Antibody–drug conjugates: Basic concepts, examples and future perspectives. Giulio Casi, Dario Neri. Journal of Controlled Release 161 (2012) 422–428
Antibody-Drug Conjugates for the Treatment of Cancer. John A. Flygare, Thomas H. Pillow and Paul Aristoff. Chem Biol Drug Des 2013; 81: 113–121