What Challenges Are Facing Antibody Drug Conjugates?
Posted: Jun 06, 2018
As perhaps the most important technique in cancer treatment, chemotherapy has been broadly employed by doctors and patients across the globe. Though effective, the accompanying side effects are huge and destructive to healthy cells. To solve this dilemma, targeted therapy makes its debut with the kindest hope that more efficacy will be achieved and less harm will be done. Antibody-drug conjugates (or ADCs) is one approach of targeted therapy.
ADCs are complex molecules composed of a monoclonal antibody linked to a biologically active cytotoxic payload or drug. In other words, there are three components in ADCs, namely, monoclonal antibody, cytotoxin and a linker. Being viewed as a promising option in anti-tumor drug development, ADCs are still facing quite a number of challenges.
Challenge 1: The Stability of ADC linkers
In contrast to the traditional chemotherapy, ADCs intends to target and kill only the cancer cells and spare healthy cells. This differentiation is made possible thanks to the tumor-specific targeting capabilities of monoclonal antibodies and the cancer-killing ability of cytotoxic drugs. However, the linker is of the same, if not more, importance as it determines the final success of an ADC.
A qualified linker should meet a lot of requirements. First, a liker should be stable in circulation which prevents healthy cells from being damaged. However, upon internalization, the linkers should perform its role properly by releasing the cytotoxic drugs in the most ideal microenvironment. The cytotoxic drug will further bind to their targets, thus making cancer cells nowhere to escape. It has been proved that the stability and rupturing capacity of linkers can affect the overall pharmacokinetics (PK) properties, toxicities and therapeutic indexes of ADCs. Whether linkers can effectively balance all these attributes is a determining factor for ADCs to enter the clinic. Some earlier ADCs (BR96-DOX and Mylotarg@, for instance) had been withdrawn from the market due to the poor stability of their linkers.
Challenge 2: ADC Killing Surrounding Cells?
Ideally, ADCs are cleaved inside the cancer cells and thus should specifically target and kill only tumor cells while leaving normal, healthy tissues unaffected. However, recent studies indicate that ADCs can be cleaved extracellularly or via other mechanisms. In such cases, the drug is then taken up by and kills surrounding cells, which themselves may or may not express the ADC target antigen.
According to an article published on Nature, some ADCs approved by FDA to enter market have also been recently reported to kill surrounding cells.
About the author
As the industry leading expert in small molecular and antibody engineering, BOC Sciences is dedicated to providing comprehensive services concerning the conjugating and characterizing of antibody drug conjugates. Whether it’s ADC cytotoxin or ADC linker, all are available at BOC Sciences.
The author is a true follower of biochemistry. BOC Sciences, the company he works for, is a trustworthy supplier of inhibitors.