The structure of Chimeric Antigen Receptor (CAR) I - Extracellular Target Antigen Binding Domains

Antigen Binding Domains

The antigen-binding domain of a chimeric antigen receptor is like the head of a train. It determines the target antigen specificity. 

The antigen-binding site is made up of a heavy chain and a light chain joined together to form a single-chain variable fragment (scFv). 


Single-chain variable fragment (scFv)

scFv targets extracellular surface cancer antigens, the biomarkers of the tumor cells. Classically, CD19 is presented in B cells in leukemia. Hence, CD19 is the biomarker that we want the CAR to recognize and bind with it.

Once the scFv of a CAR binds with the target antigen, the immune response, major histocompatibility complex (MHC)-independent T cell activation, results. This is when a cascade of molecular signaling starts to trigger an immune response to kill the tumor cells. 


MHC-dependent, T cell receptors (TCR)-mimic CARs

Some may call it an improvement, but a T cell receptor (TCR)-mimic CAR functions well when it targets intracellular tumor-associated antigens. In contrast, when extracellular surface cancer antigens are the target, MHC-independent T cell activation is a preferable choice. 


Parameter for CARs performance: affinity

Affinity is the metric used to quantify the performance and functionality of a CAR. High affinity means stronger CAR signaling and more activated T cells. However, things could go opposite when the affinity is too high - it could lead to unfavorably more activation-induced cell deaths (AICD) of T cells. This leads to toxicity and impacts the host. 

If the affinity is too low, several factors could be considered. The epitope location, the target antigen density, and the avoidance of scFv associated with ligand-dependent tonic signaling are key aspects to address to optimize CAR-Target binding. 

Comments

Post a Comment

Popular posts from this blog

What is Pepsin?

Image
In Your Body... Pepsin is a digestive enzyme that performed the best in the acidic condition (pH 2) produced by the gastric juice. It digests and breaks down protein (e.g. meat, seeds, eggs, dairy products, etc.). Keep in mind that pepsin digests proteins (not carbohydrates, not fat) into peptides. These peptides are then either absorbed in the intestine or further break down by enzymes from pancreas. In small intestine (pH around 7), pepsin is no longer effective and no longer digests proteins. Hormones Hormones that regulate digestion and hunger such as gastrin and secretin stimulates the production of pepsinogen, the proenzyme of pepsin. In other words, when pepsinogen is activated, it becomes pepsin.
Read more

The structure of Chimeric Antigen Receptor (CAR) III - Transmembrane Domains

Image
Transmembrane Domains Among the four components of a chimeric antigen receptor (CAR), the transmembrane domain is the least studied one. How different transmembrane domains affect and contribute to each other's functions is also not well studied. That being said, we will go through the function of a transmembrane domain of a CAR, the CD3ζ transmembrane domain, and the CD8α transmembrane domain.  Introduction of the transmembrane domain The transmembrane domain is where the transmembrane proteins are located. In a CAR, the transmembrane domain has the function to anchor the CAR to the T cell membrane. How strong the CAR is anchored to the T cell membrane affects the CAR expression level and stability.  Currently, the commonly used transmembrane domain is derived from proteins such as CD3ζ, CD4, CD8α, and CD28. The CD3ζ transmembrane domain Among the transmembrane domains mentioned, the CD3ζ transmembrane may improve CAR-mediated T cell action as the CD3ζ transmembrane medi...
Read more