T-cell TandAbs

Affimed’s T-cell TandAbs are exceptionally potent.
 
 
     
 
  Employing One of the Most Potent Cancer Cell-killing Mechanisms to Achieve Molecular Responses  
   
 
The destruction of "foreign" cells by T-cells is a core component of immune defense. However, cancer cells have developed ways to escape immune surveillance and thereby are not subject to an attack by T-cells. T-cell TandAbs overcome the complex network of activating and inhibitory signals directly and only at the site of a single tumor cell, where the close proximity generated by the TandAb triggers the cytotoxic effect. In the absence of a tumor cell, the T-cell is not activated.  Affimed’s development product AFM11 in phase 1 clinical development is a T-cell TandAb. It comprises two binding sites for each CD19, a B-cell epitope found on malignant cells that cause leukemia or lymphoma, and CD3, a component of the T-cell receptor. Similar to the mechanism described for NK-cell TandAbs, when the T-cell via its CD3 receptor is cross-linked by the TandAb with the tumor cell (via its CD19 antigen) it forms an immunological synapse, which generates a strong activating signal. This activating signal induces the transport of cytotoxic granules to the cell surface where they release perforin and granzyme in the vicinity of the tumor cell.   Perforin then facilitates the diffusion of granzyme into the target cell where it initiates the apoptotic pathway leading to the destruction of the cancer cell.  In the absence of a CD19-positive cell, the TandAb® does not productively cross-link the CD3 receptor on T-cells, which is an essential requirement for their stimulation, and the T-cells remain inactive. This mechanism is exceptionally potent: target-dependent cytotoxicity occurs at low picomolar concentration, which translates to therapeutic doses in the microgram range. The high potency of AFM11 is also observed at low T-cell-to-tumor cell ratios. This may be of particular benefit in patients whose immune system is compromised, e.g. by chemotherapy, or if perfusion is restricted, such as inside large tumors. Others have shown that this T-cell homing mechanism is also extremely effective in patients: none of the tumor cells appeared to have survived treatment, even using the most sensitive detection methods.  Such "deep" responses may translate into better long-term outcome.
 
  Mode of Action of TandAbs Recruiting T-cells  
   
 
     
  The T-cell TandAb directs the T-cell to binding to the tumor cell and thereby activates the T-cell to exert its cytotoxic power.

For the recruitment of T-cells, an antibody against the CD3 receptor, part of the T-cell receptor complex, is utilized that binds CD3 with nanomolar affinity. The T-cell TandAb® binds to a target cell molecule, e.g., CD19, with two of its binding sites, and to the CD3 receptor, with the other two binding sites. This cross-linking event initiates the killing activity of the respective T-cell. The resulting cytotoxic potency in cell assays is in the picomolar range.

 
 
     
  In essence, T-cell TandAbs, similar to check-point inhibitors, overcome the complex network of activating and inhibitory signals directly. However, TandAbs activate the T-cells only at the site of a single tumor cell. Granules containing cell lysing components, such as perforin, granzyme and lysosomal enzymes, are transported towards the cell membrane of the T-cell and subsequently secreted into the extracellular matrix. Perforin causes the formation of pores in the target cell, thereby facilitating the entry of the cell lysing components. This set of activities lead to tumor cell apoptosis.  
 
 
 
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