Figure 9.

Mechanism of action of high FHR4‐valence immunoconjugates to activate AP on HER2 tumours cells and CDC. Optimised high FHR4‐valence heteromultimeric immunoconjugates, but not low‐FHR4 valence counterparts, activate C3b on target tumour cells by neutralising FH, allowing overcoming FH‐mediated CIT and by directly activating the AP by allowing the formation of the FHR4‐bound C3bBb convertases. Multivalent expression of FHR4 is key to allow local selective efficient competition with FH on tumour cell surfaces. Depending on mCRP overexpression pattern on target tumours, multimer‐mediated convertase formation and subsequent MAC densities can partially be controlled, but not prevented, leading in our hands from about 100% to 60% direct lysis according to the resistance of the cell to complement attack. Finally, C3b breakdown products on opsonised tumour targets are recognised by macrophages, allowing tumour cell clearance by CDCP. FI, factor I; FD, factor D.