FcγRs and Their Relevance for the Activity of Anti-CD40 Antibodies

Abstract

Inhibitory targeting of the CD40L-CD40 system is a promising therapeutic option in the field of organ transplantation and is also attractive in the treatment of autoimmune diseases. After early complex results with neutralizing CD40L antibodies, it turned out that lack of Fcγ receptor (FcγR)-binding is the crucial factor for the development of safe inhibitory antibodies targeting CD40L or CD40. Indeed, in recent years, blocking CD40 antibodies not interacting with FcγRs, has proven to be well tolerated in clinical studies and has shown initial clinical efficacy. Stimulation of CD40 is also of considerable therapeutic interest, especially in cancer immunotherapy. CD40 can be robustly activated by genetically engineered variants of soluble CD40L but also by anti-CD40 antibodies. However, the development of CD40L-based agonists is biotechnologically and pharmacokinetically challenging, and anti-CD40 antibodies typically display only strong agonism in complex with FcγRs or upon secondary crosslinking. The latter, however, typically results in poorly developable mixtures of molecule species of varying stoichiometry and FcγR-binding by anti-CD40 antibodies can elicit unwanted side effects such as antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP) of CD40 expressing immune cells. Here, we summarize and compare strategies to overcome the unwanted target cell-destroying activity of anti-CD40-FcγR complexes, especially the use of FcγR type-specific mutants and the FcγR-independent cell surface anchoring of bispecific anti-CD40 fusion proteins. Especially, we discuss the therapeutic potential of these strategies in view of the emerging evidence for the dose-limiting activities of systemic CD40 engagement.

Genetically engineered IgG1 and nanobody oligomers acquire strong intrinsic CD40 agonism

“…ADCC, CDC, and/or ADCP. In such cases, FcγR-binding of anti-CD40 antibodies not only results in CD40 agonism but also in the killing of the CD40-expressing target cell [ 44 ]. Anti-CD40 antibody variants with robust autonomous, thus molecule-intrinsic and FcγR-independent agonism can obviously overcome these limitations and could open new avenues in the exploitation of CD40 as a therapeutic target.…”

“…The major potential therapeutic aim which could be preferentially achieved with these types of CD40 antibody constructs is certainly the stimulation of antigen-presenting cells to improve vaccination or to booster anti-tumor responses. FcγR-independent authentic CD40 agonists, as described in this study, however, are not useful when CD40 targeting is envisaged with the intention to stimulate FcγR functions, such as ADCC, ADCP, and CDC to kill tumor cells with high CD40 expression levels [ 44 ]. Worth mentioning, genetic engineering of the Fc domain of CD40, to achieve lack of FcγR binding or to reach preference for the binding of the inhibitory FcγRIIB, enables the empowerment of anti-CD40 antibodies to act together with soluble CD40L as agonists or as conditional CD40 agonists with FcγRIIB-restricted agonism [ 44 ].…”

“…FcγR-independent authentic CD40 agonists, as described in this study, however, are not useful when CD40 targeting is envisaged with the intention to stimulate FcγR functions, such as ADCC, ADCP, and CDC to kill tumor cells with high CD40 expression levels [ 44 ]. Worth mentioning, genetic engineering of the Fc domain of CD40, to achieve lack of FcγR binding or to reach preference for the binding of the inhibitory FcγRIIB, enables the empowerment of anti-CD40 antibodies to act together with soluble CD40L as agonists or as conditional CD40 agonists with FcγRIIB-restricted agonism [ 44 ]. Thus, the choice to use an authentic anti-CD40 agonist as described in this study or a certain type of conventional anti-CD40 antibody is highly dependent on the concrete therapeutic aim.…”

Perspective view of allogeneic IgG tumor immunotherapy

“…CD40 ligation could overcome peptide-induced peripheral CTL tolerance and increase antitumor efficacy [ 72 – 74 ]. Evidence suggests that the effect of anti-CD40 antibodies on CD40-expressing cells critically depends on whether they interact with FcγR and C1 [ 75 ]. Therefore, the CD40/CD40L interaction is necessary for optimal antigen presentation by DCs.…”