Scientists at antibody engineering company Xencor in Monrovia, CA have just published a research paper that cites using HemaCare sourced leukopaks in the development of their new antibody platform.
Monoclonal antibody therapy has become central to the treatment of many different diseases, including autoimmune disorders, asthma and cancer. Yet in spite of this success, many disease targets have yet to be effectively addressed. Monoclonal antibodies have trouble binding to antigens that are weakly expressed, which results in a need for higher dosing concentrations. High treatment dosages, in turn, can lead to toxicity effects. Monoclonals are also limited in that they can only block one target at a time, leaving parallel disease pathways open that can lead to treatment resistance.
To address these and other issues, scientists like those at Xencor have worked to employ strategies that circumvent these shortcomings. One promising result has been the development of bispecific antibodies. This new type of antibody is genetically engineered to simultaneously bind two different protein targets. The most widely used application for this technology is in cancer immunotherapy, where the dual-specificity of the antibodies is used to bind both the target cancer cell and a cytotoxic immune cell.
The authors aim to develop a platform that allows them to efficiently engineer bispecific monoclonal antibodies in multiple formats with different therapeutic properties. To accomplish this, they designed bispecific antibodies containing a “heterodimeric Fc region”. For those of us unfamiliar with antibody lingo, this means that the tail region of the antibody has two different side chains that can bind two different antigen targets. Each side chain of the antibody can also be engineered with a different valency (number of antigen binding sites).
Designing the antibodies this way offers several key advantages. Being able to bind specific target antigens on cytotoxic T-cells and cancer cells at the same time enables the T-cells to directly attack the cancer cell. Being able to swap antibody side chains with different valences means that affinity for a specific target can be adjusted at need, allowing for both lower dosing capability and lower off-target activity.
The authors designed a case study to test their antibody engineering platform. They obtained HemaCare leukopaks from which they purified PBMCs, and then isolated primary T cells in order to carry out their antigen binding and cytotoxicity studies. Sourcing healthy primary cells for this type of study is crucial, since reliable therapeutic potency of the purified T cells is critical in determining the efficacy of the antibody product. Rigorous testing proved that the antibodies worked just as the authors had planned. Side chain swapping could be carried out smoothly and efficiently with very low incidence of impurities. T-cell cytotoxic activity showed specificity for tumor cell lines over normal cells, and tumor cell targeting was effective at significantly lower doses than for standard monoclonal antibodies. In short, this novel platform for bispecific antibody production shows great promise for both targeting flexibility and ease of manufacturing scale-up. Individually designed bispecific antibodies are already demonstrating their utility in antibody-based cancer immunotherapy. The authors hope their new platform will rapidly enable multiple bispecific candidates to enter the clinic.
In cytotoxicity assays, HemaCare-sourced primary T cells attack antibody-labelled cells with either high (tumor cells) or low (normal cells) tumor-associated antigen density. Different antibody constructs (panels A and B) display differential activity against tumor or normal cells. Image Credit: Moore et al. 2019
- A robust heterodimeric Fc platform engineered for efficient development of bispecific antibodies of multiple formats. Methods; 154, 38-50. Feb 2019.