NK-cell TandAbs

Affimed’s NK-cell TandAb is a first-in-class molecule
with intriguing potential.

 
 
     
 
  Pioneering a Novel Approach to Selectively Direct NK cells to Eliminate Cancer Cells  
   
 
Apart from T-cells, NK-cells are the most potent cells in our immune defense arsenal. Utilizing the cytotoxic potential of NK-cells specifically through the CD16A receptor is a unique approach in cancer immunotherapy that Affimed is pioneering. Affimed’s development product AFM13 in phase 2 clinical development is a first-in-class NK-cell TandAb designed for the treatment of certain CD30-positive B- and T-cell malignancies, including Hodgkin Lymphoma or HL. The molecule comprises two binding sites for CD30, an epitope found on the tumor cells of various lymphomas, and two binding sites for CD16A, also known as FcγRIIIA. This receptor is found on NK-cells and macrophages, but not neutrophils. The NK-cell expresses various stimulatory and inhibitory receptors that regulate its activity, that allow it to distinguish between healthy cells and infected or degenerate cells. 
  When the NK-cell via its CD16A receptor is cross-linked by the TandAb with the tumor cell (via its CD30 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. The interaction of perforin with the tumor cell membrane facilitates the entry of granzyme into the tumor cell where it initiates a succession of further enzyme activities (the caspase cascade) resulting in apoptosis (programmed cell death).

AFM13, utilizing this mode of action, has already shown a favorable safety profile and promising activity in a phase 1 clinical study. AFM13 is being developed as a monotherapy (phase 2) and in combination with Merck’s Keytruda (phase 1).

 
  Mode of Action of TandAbs Recruiting NK-cells  
   
 
     
  The NK-cell TandAb directs the NK-cell to bind to the tumor cell and thereby activates the NK-cell to exert its cytotoxic power.

Affimed´s NK-cell TandAb® is able to direct NK-cells to launch an attack and eliminate cancer cells. Full-length antibodies through their Fc portion bind the Fcγ Receptor III triggering antibody dependent cellular cytotoxicity (ADCC). However, Affimed’s platform selectively targets the subtype Fcγ Receptor IIIA, which is found on NK-cells and macrophages, but not on neutrophils. Neutrophil-binding significantly dilutes the immune response, as neutrophils do not have the ability to kill tumor cells. Furthermore, Affimed’s NK-cell TandAbs bind to the FcγRIIIA with sub-nanomolar affinity, approximately 1,000-fold stronger than regular antibodies.
 
 
     
  For the binding of NK-cells, Affimed has developed a highly specific and potent antibody against the FcyRIIIA (CD16A) receptor. The NK-cell TandAb binds to a target cell molecule, e.g., CD30, with two of its binding sites, and simultaneously to the CD16A receptor, with the other two binding sites. This cross-linking event initiates the killing activity of the respective NK-cell. Granules containing cell lysing components, such as perforin, granzyme and lysosomal enzymes, are transported towards the cell membrane of the NK-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.  
 
     
 
 
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