Antibody Drug Conjugates: Trying to Answer an Eternal Question

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Sweet Syndrome: A Zebra to Consider
Sweet Syndrome: A Zebra to Consider

I was recently interviewing a new clinic patient about her cancer history and prior chemotherapy regimens.  After filing through hundreds of pages of old charts and asking a long list of questions, the patient appeared visually distraught. I quickly acknowledged her obvious frustration with the time spent compiling her history, but it appeared there was a deeper issue. I was able to ascertain that her primary source of anguish was over her previous chemotherapeutic regimens, and their draining side effects. At one point, she asked with a smirk, “With all that schooling, can't you doctors just make a medicine that just kills the cancer instead of the small amount of good things I got left like my hair?”

I realized she was joking, however, I did admit to her that she raised a good point. After years of doctor visits, blood tests, and chemotherapy infusions, this patient had asked the question that millions of people, including patients and healthcare professionals alike, wish they had the answer to. I offered reassurance that the answer to her question was far more complicated than expected, but that new innovations in clinical research could provide the answer that we are all looking for.

Recently, there have been reports of a new medication called T-DM1 (Trastuzumab Emtansine), an analog of the HER-2 receptor monoclonal antibody (mAb) Trastuzumab. Results from the EMILIA study presented at last week's ASCO meeting showed that T-DM1 had less disease progression or death, higher one- and two-year survival rates, and less severe toxicities when compared to Capecitabine plus Lapatinib. T-DM1 uses a specific type of technology called Antibody Drug Conjugates (ADC) which links mAbs to a “conjugate” and delivers it to a specific type of cancer cell. Conjugates can include cytotoxic agents, RNAses and radionuclides. The strategy behind this drug-delivery system is to use the mAb to carry the toxin, a maytansine derivative in the case of T-DM1, specifically to the cancer cell while avoiding normally functioning cells, and the resulting side effects. Once the mAb binds to its specific receptor, the entire molecule is endocytosed and transported to the lysosome which is responsible for breaking the linker between the mAb and its respective conjugate. Once released from the mAb, the conjugate reacts within the target cell leading to cell-cycle arrest or apoptosis. Several other toxins are currently being studied as conjugates, including monomethyl aurostatin E (MMAE) and mesothelin. 

The concept of ADC in oncology is not a new one; however, the recent T-DM1 results have made it re-emerge as a unique way to administer cancer-treatment drugs. Aside from boosting efficacy and limiting side effects, the ADC concept has unlimited potential for future drug development. Preclinical and Phase 1 data from new ADC compounds could provide a more accurate guide to efficacy and safety monitoring for Phase 2 and 3 studies, and less attrition of new chemical entities.

Medications that had initial success but now have growing resistance could be candidates for “revitalization” with conjugates, such as with Trastuzumab. Instead of spending billions of dollars on developing a brand-new drug, medications already on the market, or previously abandoned due to unsafe profiles could be used as templates for conversion to an ADC. More studies are obviously needed, however the promise that the ADC concept has had for years could finally be coming to fruition. 

Have your patients been asking about the T-DM1 data, and what makes it different than traditional chemotherapy?

What challenges do you foresee with administering ADC compounds like T-DM1?

Readers: We'd love to hear from you in the comments section below! If you have a case study or a more extended response to this subject, click here to submit an item for us to publish


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