Figure 7.

39S and trastuzumab epitopes are located at opposite ends of HER2 molecule at a distance of more than 90 Å from each other (black line). The (G₄S)₃ linker employed in MEDI4276 can hardly stretch to even 60 Å and will not be able to cover the distance of 98 Å (green line) that would be required to allow the C-terminal residue of trastuzumab scFv and N-terminal amino acid of 39S heavy chain to bind simultaneously to the same antigen molecule. This suggests that MEDI4276 cannot bind two HER2 receptors and have all its paratopes occupied at the same time.