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. 2013 Mar 1;19(5):1035-43.
doi: 10.1158/1078-0432.CCR-12-2064.

Agonistic CD40 antibodies and cancer therapy

Robert H Vonderheide  1 , Martin J Glennie
Affiliations

Agonistic CD40 antibodies and cancer therapy

Robert H Vonderheide et al. Clin Cancer Res. .

Abstract

Recent success in cancer immunotherapy has reinvigorated the hypothesis that the immune system can control many if not most cancers, in some cases producing durable responses in a way not seen with many small-molecule drugs. Agonistic CD40 monoclonal antibodies (mAb) offer a new therapeutic option which has the potential to generate anticancer immunity by various mechanisms. CD40 is a TNF receptor superfamily member expressed broadly on antigen-presenting cells (APC) such as dendritic cells, B cells, and monocytes as well as many nonimmune cells and a range of tumors. Agonistic CD40 mAb have been shown to activate APC and promote antitumor T-cell responses and to foster cytotoxic myeloid cells with the potential to control cancer in the absence of T-cell immunity. Thus, agonistic CD40 mAb are fundamentally different from mAb which block negative immune checkpoint such as anti-CTLA-4 or anti-PD-1. Initial clinical trials of agonistic CD40 mAb have shown highly promising results in the absence of disabling toxicity, both in single-agent studies and in combination with chemotherapy; however, numerous questions remain about dose, schedule, route of administration, and formulation. Recent findings about the role played by the IgG isotype and the Fc gamma receptor (FcγR) in mAb cross-linking, together with insights into mechanisms of action, particularly with regard to the role of myeloid cells, are predicted to help design next-generation CD40 agonistic reagents with greater efficacy. Here, we will review the preclinical and clinical data and discuss the major issues facing the field.

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Figures

Figure 1
Figure 1. Potential mechanisms of action of agonistic CD40 mAb on various immune effectors
The primary consequence of CD40 mAb is to activate DC (often termed licensing) (first panel) and potentially myeloid cells and B cells (not shown) and increase their ability to process and present Tumor-Associated Antigens (TAA) to local CTLs. Work from numerous model systems suggest that DC are the most potent in performing this function and show that only in tumors which are relatively immunogenic and hence have sufficient on-going immune recognition will control be established with this treatment. Recent data from genetic tumor models now underscore the ability of agonistic CD40 mAb to generate tumoricidal myeloid cells (middle panel) when CTL responses cannot be established. Finally, agonistic CD40 mAb can have a cytotoxic effect on tumor by initiating ADCC, CMC or program cell death (PCD) (third panel (tumor)). It is not clear to what extent anti-CD40 mAb can promote cell death in solid tumors, but hematological malignancies are susceptible to killing. Tumor associated antigens released from dead and dying tumor cells (panel 3 (tumor) have the potential to be cross-primed by APC and presented to CTL (panel 1) without the need for T-cell help.
Figure 2
Figure 2. Binding affinities of mouse, rat and human IgG to mouse and human Fcγ receptors
The values for the mouse IgG binding to mouse FcgR are taken from Nimmerjahn et al (58) and White et al (31). The values for rat IgG2a binding to mouse FcgR are provided by Dr Ian Mockridge (University of Southampton). The values for the human IgG and FcγR are taken from Bruhns et al (33). Mouse IgG1 and rat IgG2a, which are highly agonistic as anti-CD40 reagents, bind to the inhibitory FcγRII with modest affinity (yellow box) but not to the activatory FcγR, FcγRI or IV. A similar isotype does not exist in humans making it difficult to select an isotype with similar agonistic properties. It is important to note that the affinity measurements for FcγR:IgG binding can show considerable variation, depending on the methods used. Thus while the relative affinities are correct the exact values are subject to experimental differences. ** Affinity values: a KA value of 650 in the table equates to 6.5 × 107 M−1. Where a range of affinities is shown this indicates measurements from different publications or binding to different alleles of certain human FcγR, such as FcγRIIa and FcγRIIIa. ND: not determined. No bind: indicates that an affinity measurement could not be made due to low binding.
Figure 3
Figure 3
Schematic demonstrating that, at least in mice, strong binding of mAb to the activatory FcγR (IgG2a) will favor cytotoxic activity via recruitment of cellular effectors, such as NK and macrophages. In contrast, mAb which bind more strongly to the inhibitory FcγR, FcγRIIb (IgG1) will be stronger agonist ideal for crosslinking TNFR molecules and promoting Ab and T-cell responses. On-going work is underway to demonstrate if similar properties can be exploited with human mAb.
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