Optimising CDC
CDC has been recognised as an important mechanism of action for some
therapeutic mAbs such as anti-CD2024–26. Thus,
strategies to optimise Fc-mediated complement activation are currently
being developed.
Intrinsically, due to its naturally occurring pentameric and hexameric
forms, IgM demonstrates the highest capacity for complement activation.
However, IgM has not received much attention in therapeutic mAbs
development and only a few tumour-targeting IgM mAbs have been evaluated
in clinical trials27; most prominently with PAT-SM6
receiving orphan drug designation by EMA and FDA for multiple
myeloma28,29.
Among IgG subclasses, IgG1 and IgG3 are good complement activators.
Although IgG3 seems to be more potent, manufacturing issues, instability
and shorter in vivo half-life make it a less attractive candidate
for drug development. A way to combine the advantages of both IgG1
(favourable manufacturing characteristics) and IgG3 (enhanced CDC) was
achieved through the construction of IgG1/IgG3 chimeric
antibodies30. The optimal construct, called 113F,
combined the CH1 and the hinge of IgG1 with the CH2 of IgG3 and a CH3
which was partly of IgG3 and partly of IgG1 origin. The nonfucosylated
version of this chimeric antibody showed enhanced CDC and ADCC
comparable to nonfucosylated IgG1, in addition to preserved protein A
binding, important for the purification process. The improved efficacy
of this chimeric construct was confirmed in cynomolgus monkeys where an
anti-CD20 113F antibody construct showed greater B-cell depletion if
compared to IgG1 (both antibodies were nonfucosylated for improved
ADCC). This study indicates that the combination of optimised complement
activation and A/I ratio represents a promising strategy for the
improvement of tumour-depleting antibodies.
Other strategies for enhanced complement activation include the
introduction of point mutations to improve IgG1 binding to
C1q16, a key component for the initiation of the
complement cascade. Importantly, mutations that potentiate CDC can be
combined with ADCP and ADCC-enhancing mutations in a single
IgG131, thus broadening the effector function of these
antibodies. Finally, the mutations that favour IgG hexamer formation
also significantly enhance C1q fixation and thus
CDC32,33. However, currently it remains to be seen
whether these Fc mutations that enhance CDC in in vitro and inex vivo studies translate into improved clinical efficacy.