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Agonistic CD40 Antibodies and Cancer Immunotherapy

Immunotherapy is an emerging alternative or adjunct to traditional cancer therapies, its goal being to stimulate a potent and specific anti-tumor immune response. The agonistic anti-CD40 monoclonal antibody is one of the most promising immunotherapies tried so far in animal models. It activates or modulates many different cells that express surface CD40 molecules, such as dendritic cells (DCs), B cells, and tumor-associated endothelial cells, all of which play an important role in driving and/or regulating effective anti-cancer immune responses. Use of agonist anti-CD40 antibody exploits natural CD40-CD40L interactions that may be seen, for example, in viral infections, wherein CD40-stimulated DCs ensure the generation of antigen-specific CTLs. Treatment with anti-CD40 monoclonal antibodies has been exploited in some cancer immunotherapy studies in mice and led to the development of anti-CD40 antibodies for clinical use.

Role of CD40 in immune responses

CD40 is a tumor necrosis factor receptor (TNFR) family member that conveys signals regulating diverse cellular responses, ranging from proliferation and differentiation to growth suppression and cell death. First identified and functionally characterized on B cells, CD40 is expressed on many other cell types, including macrophages, endothelial cells, dendritic cells (DCs), and fibroblasts. This widespread expression accounts for the central role of CD40 in the regulation of immune response and host defense. Binding of CD40 with its counter receptor, CD154 acts on antigen-presenting cells (APCs) and T cells in a bidirectional fashion, mediating both humoral and cellular immune responses. CD154 on activated T cells induces clonal expansion of B cells (or in some cases clonal deletion of desensitized B cells). It also induces immunoglobulin class switching, and humans with a mutation of CD154 develop hyper-IgM syndrome and are unable to mount effective IgA, IgG, or IgE responses. B cells depend on CD40 for survival, for expression of costimulatory molecules like B7 (to interact with T cells), germinal center formation, memory generation, and production of numerous cytokines and chemokines (interleukin [IL]-1, IL-6, IL-8, IL-10, IL-12), tumor necrosis factor-α (TNF-α), macrophage inflammatory protein-1α (MIP-1α), and cytotoxic radicals.

Mechanisms of action of agonistic CD40 mAb

Although the primary mechanistic rationale invoked for agonistic CD40 mAb is to activate host APC, especially DC, to induce clinically meaningful antitumor T-cell responses in patients, other immune mechanisms that are not necessarily mutually exclusive have been proposed (Figure 1). These include T-cell–independent but macrophage-dependent triggering of tumor regression. CD40-activated macrophages can become tumoricidal, and at least in pancreatic cancer may also facilitate the depletion of tumor stroma, which induces tumor collapse in vivo. Importantly, these mechanisms do not require expression of CD40 by the tumor, which has justified the inclusion of patients with a broad range of tumors in many of the clinical trials. Insofar as these strategies aim to activate DC, macrophages, or both, the goal is not necessarily for the CD40 mAb to kill the cell it binds to, for example, via complement-mediated cytotoxicity (CMC) or antibody-dependent cellular cytotoxicity (ADCC). Thus, by design, the strong agonistic mAb CP-870,893 is a fully human IgG2 molecule, which does not mediate CMC or ADCC. In contrast, other human CD40 mAb used to date have been of the IgG1 isotype and therefore more able to mediate CMC and ADCC against CD40+ tumors, such as nearly all B-cell malignancies, a fraction of melanomas, and between 40% and 75% of carcinomas (Figure 1).

Figure 1. Potential mechanisms of action of agonistic CD40 mAb on various immune effectors.

Anti-CD40 mAb in development

The therapeutic anti-human CD40 mAbs Dacetuzumab and Lucatumumab are recombinant antibodies and have become the leading drug candidates in relation to anti- CD40 based immunotherapy. Dacetuzumab is a humanized anti-CD40 agonistic mAb that triggers CD40-mediated signaling in various cells. Lucatumumab is a fully humanized antagonistic antibody against CD40 and exerts its primary function through opsonization followed by ADCC (Figure 2). In fact, blocking the potential CD40-CD40L tumor growth signal has been a rationale for developing the CD40 antagonistic mAb Lucatumumab in diseases such as chronic lymphocytic leukemia. Immunologically, direct tumor cytotoxicity accomplished by CD40 agonists is hypothesized to provide a source of tumor antigen that can be processed and presented by host APC which are simultaneously activated by the same intervention. This "two-for-one" mechanism postulated for strong CD40 agonists has provided further justification for single-agent clinical trials, even though it seems likely that combining CD40 mAb with strong vaccines or cytokines may be clinically more potent for driving an adaptive antitumor immune response.

Figure 2. Promising drug candidates targeting CD40.

Administration of anti-CD40 mAb is most commonly systemically, e.g. by i.v. administration, but in some cases injection directly into the tumor has been tested and may result in a better therapeutic response. It has been postulated, that a part of this beneficial effect is due to a slow release of the mAb which may prolong access for effector cells and at the same time reduce antibody-mediated side-effects and toxicity.

Summary

The agonistic CD40 mAb represents a promising strategy for novel cancer therapeutics. Preclinical investigations with CD40 agonists have been robust and highlight multiple mechanisms of action including activation of APC that drives antitumor T cells, activation of macrophages that are tumoricidal, and induction of apoptosis in CD40+ tumor cells such as lymphoma or certain solid tumors. Initial clinical trials of agonistic CD40 mAb have shown clinical activity in the absence of disabling toxicity. Some clinical responses have been dramatic and very durable, but response rates remain 20% or less. It seems likely that at least for solid tumors, agonistic CD40 mAb will be most effectively used in combination with other modalities, such as chemotherapy, radiation, or vaccines; however, single-agent therapy for B-cell lymphoma remains an important possibility.

It is important that agonistic CD40 mAb as immunostimulatory agents strikingly differ in their proposed mechanism of action compared with mAb that accomplishes immune activation by blocking negative checkpoint molecules such as CTLA-4 or PD-1. In fact, the prospect of combining agonistic CD40 mAb with anti- CTLA-4 or anti-PD-1 mAb is enticing and represents a real immunologic opportunity to "step on the gas" while "cutting the brakes." Therefore, combinations of novel immunotherapy—especially immunomodulatory mAb—is an important goal.

References:
1. Fonsatti E, et al. Biology and clinical applications of CD40 in cancer treatment. Seminars in Oncology, 2010, 37(5):517-523.
2. Richman L P, Vonderheide R H. Role of crosslinking for agonistic CD40 monoclonal antibodies as immune therapy of cancer. Cancer Immunol Res, 2014, 2(1):19-26.
3. Khong A, et al. The use of agonistic anti-CD40 therapy in treatments for cancer. International Reviews of Immunology, 2012, 31(4):246-266.
4. Vonderheide R H, Glennie M J. Agonistic CD40 Antibodies and Cancer Therapy. Clinical Cancer Research, 2013, 19(5):1035-1043.
5. Hassan S B, et al. Anti-CD40-mediated cancer immunotherapy: an update of recent and ongoing clinical trials. Immunopharmacology & Immunotoxicology, 2014, 36(2):96-104.
6. Kedar R, et al. Soluble CD40 ligand (sCD40L) provides a new delivery system for targeted treatment: sCD40L-caspase 3 chimeric protein for treating B-cell malignancies. Cancer, 2012, 118(24):6089-6104.
7. Beatty G L, et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science, 2011, 331(6024):1612-1616.
8. Eliopoulos A G, Young L S. The role of the CD40 pathway in the pathogenesis and treatment of cancer. Current Opinion in Pharmacology, 2004, 4(4):360-7.

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