Locally Delivered CD40 Agonist Antibody Accumulates in Secondary Lymphoid Organs and Eradicates Experimental Disseminated Bladder Cancer

Abstract

Immunotherapy with intratumoral injection of adenoviral vectors expressing CD40L has yielded positive results in experimental and clinical bladder cancer. We therefore hypothesized that anti-CD40 antibody would be effective in this setting. Agonistic CD40 antibodies were developed as vaccine adjuvants but have later been used as treatment of advanced solid tumors and hematologic cancers. Systemic anti-CD40 therapy has been associated with immune-related adverse events, such as cytokine release syndrome and liver toxicity, and local delivery is an attractive approach that could reduce toxicity. Herein, we compared local and systemic anti-CD40 antibody delivery to evaluate efficacy, toxicity, and biodistribution in the experimental MB49 bladder cancer model. Antitumor effects were confirmed in the B16 model. In terms of antitumor efficacy, local anti-CD40 antibody stimulation was superior to systemic therapy at an equivalent dose and CD8 T cells were crucial for tumor growth inhibition. Both administration routes were dependent on host CD40 expression for therapeutic efficacy. In vivo biodistribution studies revealed CD40-specific antibody accumulation in the tumor-draining lymph nodes and the spleen, most likely reflecting organs with frequent target antigen-expressing immune cells. Systemic administration led to higher antibody concentrations in the liver and blood compared with local delivery, and was associated with elevated levels of serum haptoglobin. Despite the lack of a slow-release system, local anti-CD40 therapy was dependent on tumor antigen at the injection site for clearance of distant tumors. To summarize, local low-dose administration of anti-CD40 antibody mediates antitumor effects in murine models with reduced toxicity and may represent an attractive treatment alternative in the clinic. Cancer Immunol Res; 2(1); 80-90. Ó2013 AACR.

The Human Agonistic CD40 Antibody ADC-1013 Eradicates Bladder Tumors and Generates T-cell–Dependent Tumor Immunity

“…Our pharmacokinetic measurements demonstrate that the distribution of ADC-1013 is highly target dependent, which is in line with previous work on murine CD40 agonistic antibodies (4). This strong target-mediated effect on the serum levels of ADC-1013 is likely a result of the target distribution, redistribution, and antibody internalization following administration (4,42). Antidrug antibodies are not likely to affect the measurements, since samples were taken within 3 days after the first treatment (4).…”

“…2). The indirect antitumor immune effect, which is independent of the CD40 status of the tumor, is mediated by tumor-specific cytotoxic T lymphocytes (4)(5)(6), and possibly macrophages in certain tumor types (7). The direct tumoricidal effects, on the other hand, depend highly on the CD40 expression of the tumor.…”

“…Systemic administration of CD40 agonists may result in dose-limiting immune-related adverse effects, such as cytokine release syndrome (12,13). Recently, it was demonstrated that local administration of agonistic CD40 antibodies into tumorbearing mice resulted in improved antitumor effect, and caused less adverse immune-related events than systemic treatment (4,14,15). The concept of intratumoral CD40 stimulation has also been validated using local injection of adenoviral vectors expressing CD40L, demonstrating antitumor effects in human and murine bladder cancer as well as in dog melanoma, with minimal side effects (16,17).…”

A Short History of the B-Cell-Associated Surface Molecule CD40

“…In particular, CD40 ligation can promote the activation of cytotoxic CD8 T cells (38), essential for effective therapeutic vaccines. Local administration and slow release of anti-CD40 may mitigate the potential adverse side effects associated with agents that strongly modulate the immune system (51, 52). Thus, it is very likely that one or more new CD40-based therapies will be in use in the coming decade.…”

Kick-starting the cancer-immunity cycle by targeting CD40

“…Intratumoral administration will in addition result in the preferential activation of dendritic cells in the tumor microenvironment, as demonstrated in preclinical models. [5][6][7][8] This is expected to reduce immune-related adverse effects and possibly increase efficacy.…”