Monomethyl auristatin F (MMAF) is a synthetic anti-tumor drug that has been used as a cytotoxic payload molecule in at least six ADCs, and these ADCs have entered clinical trials.

Structure of MMAF

MMAF is a new auristatin derivative with a similar structure to MMAE. The difference between MMAF and MMAE is that the C-terminal of MMAF has a phenylalanine moiety, which can reduce its cytotoxicity and enhance its membrane impermeability. The N-terminal amino group of MMAF has only one methyl substituent.

Figure 1: Structure of MMAF.

Biological Activity of MMAF

Monomethylastatin F (MMAF) is an anti-mitotic agent that inhibits cell division by preventing the polymerization of tubulin. Due to its extremely high toxicity, it cannot be used as a medicine by itself. It is linked to monoclonal antibodies (mAbs) that direct it to cancer cells. The monoclonal antibody linker is stable in the extracellular fluid, but once the conjugate enters the tumor cell, cathepsin will cleave the conjugate, thereby activating the anti-mitotic mechanism.

Figure 2: Structure of a MMAF-mAb-conjugate (from Wikipedia).

ADCs drugs with MMAF