Enhancing Antibody Potency

Although antibodies are an effective class of therapeutics, there is certainly room for increasing their potency. This is especially true in the field of cancer therapy. The response rate of antibodies, either as single drugs or in combination with chemotherapy, ranges from 10 to 50%.
Existing antibody oncologics work by interrupting essential signaling pathways, such as the epidermal growth factor receptor signaling family, and/or by eliciting ADCC, CDC or apoptosis. There are a number of approaches under investigation to enhance antibody potency by either conjugating antibodies to toxic compounds or by engineering the Fc portion of the antibody to increase ADCC or CDC.
The concept of enhancing antibody potency via delivery of a toxic payload dates to the time of Ehrlich, at the turn of the 20th century. Ehrlich conceptualized magic bullets, molecules that could selectively target a disease-causing organism and deliver a toxic payload. One of the first examples of such antibody delivery of toxic payloads are immunotoxins, antibodies or antibody fragments fused to toxins. Toxins that have been utilized, such as Pseudomonas exotoxin, are
highly toxic, with just a few molecules being capable of cell killing.
Therapeutic development of immunotoxins has required overcoming a number of obstacles, including immunogenicity of bacterial and plant toxins when administered to humans, the high toxicity of the toxins used for immunotoxin construction and the development of methods to fuse toxins to antibodies or antibody fragments. scFv antibody fragments are natural fusion partners for toxins allowing the immunotoxin to be encoded in a single gene and expressed as a single polypetide chain. Although immunogenicity still remains an issue, immunotoxins are now in clinical trials for cancer and may be especially efficacious against hematological malignancies. An alternative approach is to fuse potent chemotherapeutic drugs directly to antibodies rather than toxins. Such antibody–drug conjugates also show dramatic therapeutic affects in preclinical models and are currently in human clinical trials as cancer therapies.
An alternative way to increase the potency of antibodies is to enhance their inherent cell killing activities that occur via the Fc portion of the antibody and Fc receptors. This interaction is responsible for antibodydependent cellular cytotoxicity (ADCC) and complement-dependent cellular cytotoxicity (CDC). The Fc binds to both activating and inhibitory Fc receptors and, depending on the affinity of the specific interactions, cell killing occurs. Recently, it has proven possible to engineer the Fc to bind activating Fc receptors more efficiently compared with inhibitory Fc receptors. Such engineered Fcs show enhanced ADCC in preclinical models of cancer and will be evaluated for enhanced efficacy in human clinical trials.