New paper by the Varani Lab
on Wednesday, July 26, 2017
The human immune system is trained to recognize and attack foreign pathogens such as viruses or bacteria but it often fails to recognize cancer cells. In recent years, scientists have been able to construct “artificial” immune cells, called Chimeric Antigen Receptors (CAR), with the ability to target cancers. Malignant cells have specific surface proteins that are not present on healthy cells; these proteins can be recognized and targeted by specific antibodies; attaching such antibodies to an immune cell allows it to recognize and subsequently kill the cancer cell. This particular type of immunotherapy has great potential and is, in some cases, at the clinical trial stage. One of the main obstacles, however, is that the protein markers (antigens) abundantly present on cancer cells are also present, albeit at lower concentration, on healthy cells. This results in undesired targeting and killing of healthy cells in a process called “on target off tumour effect”.
In a recently published paper Varani and coworkers, in collaboration with clinical researchers of the Centro Ricerca Tettamanti, described how the activity of a targeting antibody can be modulated to achieve optimal recognition of cancer cells while sparing healthy ones. The IRB researchers developed and produced an antibody that directs artificial immune cells (CAR) against Acute Myeloid Leukemia (AML) cells. Using computational and experimental structural biology strategies they then modified the antibody so that it could bind more or less strongly to its target on AML cells. They demonstrated that antibodies that strongly bind (technically they have a strong binding affinity) to their target cannot effectively distinguish cancer from healthy cells. Weaker binding, instead, maintains efficient killing of human leukemia cells while sparing healthy control tissue. They also showed that the amount of targeting antibody molecules present on the immune cells has a profound effect on the efficient targeting of AML cells. The work suggests that when designing a Chimeric Antigen Receptor for the treatment of acute myeloid leukemia, and possibly against any other target, efforts should be directed towards the development of antibodies that bind relatively weakly to the cancer antigens but are abundantly present on the artificial immune cells.
Balance of Anti-CD123 Chimeric Antigen Receptor Binding Affinity and Density for the Targeting of Acute Myeloid Leukemia.
Arcangeli, S., M. C. Rotiroti, M. Bardelli, L. Simonelli, C. F. Magnani, A. Biondi, E. Biagi, S. Tettamanti and L. Varani
Mol Ther. 2017;