Can We Finally Win the “War Against Cancer” with Antibody-drug Conjugates?
The greatest problems with cancer treatment lie in their nonspecificity: cancer cells can be difficult to target and in the process of targeting them, therapies often kills healthy cells. In designing newer interventions, pharmaceutical companies and research organizations see much potential in the development of antibody-drug conjugates, monoclonal antibodies that allow “sensitive discrimination between healthy and diseased tissue.”1 Beyond being able to detect the differences between cancer and normal cells via antibody binding, antibody-drug conjugates can deliver chemotherapy drugs directly to cancer cells upon binding, where linkers prevent the chemotherapy agent from leaving the antibody before it reaches cancerous cells.2 This three-pronged approach of delivering a monoclonal antibody, linker and chemotherapy drug directly to a specific site has been heralded as the “magic bullet” approach to treating cancer.3
Not All that Glitters Is Gold: Complications with Antibody-drug Conjugates
Despite the promise of antibody-drug conjugates, less than 1 percent of the chemotherapeutic drug actually makes it to the tumor. Unfortunately, without reaching the tumor site and binding specifically to receptors on cancer cells, antibody-drug conjugates are like “floating sea mines,” destined to never quite “blow up.”4 In order to improve the efficacy of these treatments, researchers must consider better ways to get more of the drug directly into the tumor:
Tumor target binding: One way to increase the amount of drug delivered to the tumor site is to increase the binding efficiency of the monoclonal antibody portions of the antibody-drug conjugates to the tumor cell. This involves identifying antigens that are very highly expressed in tumor cells (high target expression of a receptor, for example, is critical), but have low-levels of expression in other cell types. As the antibody-drug conjugates travel throughout the body, with such a high affinity for the specific tumor cell receptors, they are less likely to bind to other cells and dilute the concentration of the antibody. To identify higher affinity antibodies, companies should keep records of antibody sequence data to identify regions of the antibody-drug conjugate that interact with the cancer cells receptor and see if these regions can be altered to increase binding activity.
Chemotherapy agent: The chemotherapy agent delivered to to the tumor can also be made more potent. Attached to the antibody-drug conjugates that must travel through the bloodstream, molecules of the agent could diffuse away. Regardless, if the chemotherapy agents that remain are strong enough, they should completely penetrate identified cancer cells and thus deliver the cytotoxic drug directly to the cancer site. To test for more potent agents, scientists can use cell assays to identify characteristics such as binding affinity, toxicity, etc. As well, increasing the cytotoxicity of the chemotherapeutic agent might require more regulatory compliance requiring that projects are carefully tracked and data is shared throughout an organization.
Linker: The linker that binds the chemotherapy agent to the monoclonal antibody is determined after carefully considering various aspects of conjugation chemistry and is “as vital as the antibody and payload for maximization of therapeutic efficacy.” By increasing the strength of linkers, researchers could potentially prevent the chemotherapy agent from drifting away from the drug-antibody complex. Indeed, one should note that an antibody-drug has failed in Phase II clinical trials for metastatic breast cancer due to the “low potency of [the anti-cancer drug] as the payload and to the instability of the linker.” A burgeoning area of research concerning linkers is the prediction of the best linker-payload combinations for antibody-drug conjugates.
These three factors are an essential component of antibody engineering, which includes inserting unusual amino acids within the antibody backbone; modifying specific amino acid sequences; or incorporating certain functional groups into the antibody backbone. But in the pursuit of the next best antibody-drug conjugates, it is necessary to keep careful records of all modifications and it would be best if these records were electronically, easily accessible by members of the engineering team and other stakeholders. As well, experiments to delineate changes in homogeneity, efficacy, tolerability and PK profiles must also be completed in order to determine how replacing glutamine tagged antibodies, for example, with amine ones, affects the general characteristics of the antibody-drug conjugate.
To organize, store, retrieve and analyze this information, BIOVIA Biologics Solution maximizes efficiency by providing a platform on which to plan and record experimental data, design workflows that can be easily modified and study high volumes of data about sequences that could inform how antibody-drug conjugates are modified. Please contact us today to learn the many more ways BIOVIA Biologics Solution can take your antibody-drug conjugates from the discovery to manufacturing stages.
- “Antibody-drug conjugates,” December 15, 2015, “https://en.wikipedia.org/wiki/Antibody-drug_conjugate ↩
- “Understanding Antibody-Drug Conjugates,” http://www.gene.com/stories/understanding-antibody-drug-conjugates ↩
- “A New Class of Cancer Drugs May Be Less Toxic,” May 31, 2012, http://www.nytimes.com/2012/06/01/business/a-new-class-of-cancer-drugs-may-be-less-toxic.html?pagewanted=all&_r=0 ↩
- “Strategies and Advancement in Antibody-Drug Conjugate Optimization for Targeted Cancer Therapeutics,” November 1, 2015, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624065/ ↩