Antibodies have transformed the way physicians treat patients with different pathologies. The next generation of monoclonal antibody (mAb) therapeutics in immuno-oncology have been optimized for safety and efficacy. Therapeutic antibodies are man-made proteins from a laboratory created to act similarly to human endogenous antibodies. The goal is to develop effective antibodies that elicit passive immunity and activate the present immune system. These “in-lab” generated antibodies are widely used across diseases, such as cancer. Mechanistically, antibodies bind to foreign invaders and neutralize infection. The elimination of inflammatory molecules protects patients from further deleterious effects of allergies and/or disease. However, there are reports in which the body misinterprets therapeutic antibodies as foreign and responds with antidrug antibodies (ADAs) to combat the treatment.
Potent immune response, especially with ADA production, can lead to anaphylaxis - a life-threatening stage of allergic reaction. ADA-driven anaphylaxis is rare and occurs randomly, making it a safety concern for patients prescribed therapeutic antibodies. Although this phenomenon has been reported, why and how ADA occurs remains unclear. Therefore, scientists have investigated ways to better elucidate this mechanism and provide insight into patient health.
To learn more, scientists in Japan investigated how lab-made antibodies interacted with immune cell respecters or FCg-receptors. These specific immune receptors help recognize antibodies and mediate robust immunity. The work was conducted at Chiba University under the supervision of Dr. Hiroto Hatakeyama in the Department of Pharmaceutical Sciences, Chiba University. Dr. Kyohei Higashi from Tokyo University of Science also collaborated to understand more about these ADA-driven anaphylactic cases.
The results were reported in the Journal for ImmunoTherapy of Cancer (JITC) demonstrating that antibody drugs with strong binding affinity to FCg-receptors were most likely to be misinterpreted as foreign, eliciting high ADA production. Specifically, researchers found that high affinity antibodies are associated with anaphylaxis.
Historically, anaphylaxis has been elicited by an upregulation of endogenous immunoglobulin E (IgE) antibodies activated by immune cells known as B lymphocytes. Consequently, IgE antibodies bind to mast cells and basophils initiating allergy symptoms through histamine release. However, this study clearly demonstrates that anaphylaxis can also occur without the need for IgE antibodies.
Experiments were performed in tumor-bearing mouse models in which two drug antibodies were tested that target programmed death-ligand 1 (PD-L1) on cancer cells. The first antibody, 10F.9G2, had strong binding affinity to FCg-receptors on immune cells and resulted in mice rapidly developing anaphylaxis. These results were accompanied by increased ADA levels suspected of causing fatality. Alternatively, antibody MIH6 had lower binding affinity and was not associated with an increase in ADA or anaphylactic reaction. To confirm these findings researchers modified 10F.9G2 to mitigate binding affinity. Consequently, these modified antibodies resulted in less ADA production and did not trigger anaphylaxis.
This work also suggested that specialized immune cells, known as myeloid cells, may regulate this process. These cells took high binding affinity antibodies and processed them to elicit a stronger immune response. Interestingly, when FCg-receptors were blocked, the anaphylactic effect was reduced. Overall, this research suggests FCg-receptors could become unique therapeutic targets to reduce anaphylaxis and offers a novel approach for patients with cancer prescribed antibody therapy.
Hiroto Hatakeyama, Department of Pharmaceutical Sciences, Chiba University, Kyohei Higashi, Tokyo University of Science, results, JITC
