THE VALUE PROPOSITION: AN ADVANCE OVER ADCs

In the last 20 years the FDA has approved over 30 antibodies. In 2011, antibody sales topped $56B. While antibodies have made a significant impact on human health, there is still ample room for improvement. This is particularly true in the cancer arena. In several cancer indications, naked antibodies have demonstrated improved efficacy over chemotherapy with the added advantage of having significantly reduced toxicities. However, for the most part efficacy is measured in terms of prolonged survival but not long term remissions or cures. Thus, the new wave of development in antibody therapeutics consists of efforts to endow antibodies with greater cell killing capability.

In the last few years, antibody drug conjugates (ADCs) have come to the fore as a new class of drugs that combine the specificity of antibodies with the killing power of potent cytotoxic small molecules. More than 30 ADCs are in development and two, Adcetris™ and Kadcyla™, have been approved. While there is tremendous excitement around this class of drugs, challenges remain. ADCs are difficult to manufacture, requiring dedicated facilities, and, because of their mechanism, are not appropriate for all cancer types. Further, cancer cells can develop resistance to the toxic small molecules over time.

Fusion toxins offer significant advantages over ADCs. Because they are typically structured as a single non-glycosylated polypeptide, fusion toxins can be made in bacterial production systems and do not require any other components or any downstream coupling reactions. Another potential advantage of fusion toxins is that they can be versatile as to the targeting component; single chain Fv fragments of antibodies have been used to good advantage, and cytokines can also be used. It is likely that many of the emerging scaffold technologies will be found to be suitable for incorporation into fusion toxins as well. Further, they are markedly more potent that ADCs, meaning that they can kill tumor cells with fewer target molecules on their surface and can be used at much lower doses. The development of fusion toxins has been held back by their immunogenicity - with repeated dosing patients develop a robust immune response to the toxin component and thereby neutralize the drug. Angelica has solved this problem.