TCR-like antibodies represent a new type of therapeutic molecule designed to target specific cells linked to various diseases, particularly cancer. These engineered antibodies combine beneficial characteristics from two natural components of the immune system: conventional antibodies and T-cell receptors. Their development marks a significant advancement in medicine, offering a way to address targets previously considered inaccessible.
The Biological Foundation for TCR-like Antibodies
Conventional antibodies, produced by B cells, primarily recognize and bind to targets found on cell surfaces or circulating freely in bodily fluids, such as viruses or bacteria. They typically identify the three-dimensional shapes of proteins or other molecules.
In contrast, T-cell receptors (TCRs) recognize targets in a more specialized way. T cells “see” small fragments of proteins, called peptides, displayed on cell surfaces by Major Histocompatibility Complex (MHC) molecules. This unique recognition allows T cells to detect internal abnormalities within cells, such as those caused by viral infections or cancerous transformations.
A significant challenge in treating diseases like cancer and chronic viral infections is that many disease-causing proteins are located inside cells, making them invisible to traditional antibody therapies. TCR-like antibodies were developed to overcome this, combining the broad applicability of antibodies with the precise intracellular targeting ability of T-cell receptors.
How TCR-like Antibodies Function
TCR-like antibodies are engineered to mimic the specific recognition capabilities of T-cell receptors. They bind precisely to peptide-MHC (pMHC) complexes displayed on target cell surfaces. This allows them to recognize protein fragments originating from inside the cell, processed and presented by MHC molecules.
Once a TCR-like antibody binds to its specific pMHC target on a diseased cell, it triggers the immune system to eliminate that cell. This can occur through mechanisms like antibody-dependent cellular cytotoxicity (ADCC), where immune cells such as natural killer (NK) cells destroy the tagged cell. Or complement-dependent cytotoxicity (CDC), involving a protein cascade that damages the target cell membrane. Some TCR-like antibodies can also directly induce programmed cell death, known as apoptosis, in the target cell.
The precise targeting by TCR-like antibodies is an advantage, as they recognize specific peptide fragments unique to diseased cells, such as those found in tumors or virus-infected cells. This specificity helps ensure healthy cells are largely spared, reducing potential side effects. Their development often involves techniques like phage display and affinity maturation for high binding affinity and specificity.
Therapeutic Potential and Unique Benefits
TCR-like antibodies offer therapeutic potential, particularly in cancer immunotherapy. They can target cancer-specific intracellular proteins, such as NY-ESO-1, MAGE-A, and WT1, which are overexpressed or mutated in tumor cells and remain inaccessible to conventional antibody drugs. This ability to target previously “undruggable” intracellular antigens is a breakthrough in cancer treatment.
The specificity of TCR-like antibodies for disease-related peptide-MHC complexes contributes to their benefits. This precision can lead to fewer off-target effects compared to some broader cancer treatments. Beyond cancer, they also hold promise for treating chronic viral infections, where infected cells present viral peptides on their surface.
Unlike personalized cell therapies, such as CAR-T or TCR-T cell therapies, TCR-like antibodies are antibody-based drugs manufactured in larger quantities. This “off-the-shelf” potential makes them more accessible for widespread clinical use. These antibodies can be used alone or in combination with other existing therapies, enhancing overall treatment efficacy.