Background CD40 is a co-stimulatory receptor of the TNF receptor superfamily expressed on antigen presenting cells (APCs). Antibodies targeting CD40 may have antitumor therapeutic benefit by driving innate immune cell activation that supports generation of antigen-specific T cell responses. Multiple CD40-directed antibodies are in clinical development in both solid and hematologic indications and differ according to immunoglobulin isotype, affinity to CD40, and differential FcγR-binding. SEA-CD40 is an agonistic nonfucosylated, humanized IgG1 monoclonal antibody directed against CD40. SEA-CD40 is distinct from other CD40 targeted agents in clinical development as it binds with increased affinity to FcγRIIIa resulting in enhanced effector function and CD40 agonism. This unique composition of SEA-CD40 could amplify immune stimulation and antitumor activity relative to other CD40-directed therapeutics.

Methods Effective immunity requires the presence of diverse antigens to drive generation of distinct antigen-specific memory T cells. SEA-CD40 in many ways works like a vaccine as it can increase active acquired immunity against endogenous tumor antigens. A potential limiting factor for maximal SEA-CD40 antitumor activity across multiple tumor types may be the limited level and diversity of tumor-associated antigens within the tumor microenvironment (TME). Chemotherapeutic agents drive tumor cell death resulting in the release and increase of tumor antigens locally within the TME. Combining chemotherapeutic agents with SEA-CD40 could facilitate robust antigen release and amplified presentation of those antigens to CD8+ T cells. Antitumor activity and immune cell changes of SEA-CD40 in combination with chemotherapeutic agents was evaluated in vitro and in vivo using human CD40 transgenic mice.

Results In preclinical mouse models, SEA-CD40 combined with chemotherapeutic agents to drive robust anti-tumor activity. The nature of the chemotherapeutic agent influenced immune cell activation within the tumor microenvironment (TME) and extent of combinability with SEA-CD40. Preclinical assessment indicates that chemotherapeutics which induce immunogenic cell death (ICD) combine with SEA-CD40 to increase curative activity compared to non-ICD-inducing chemotherapeutics. The preferred partnership of SEA-CD40 with ICD-inducing agents, such as a monomethyl auristatin E (MMAE) antibody-drug conjugate, increased curative antitumor activity in mouse models. The combination of SEA-CD40 and chemotherapeutic agents with a T cell targeted anti-PD1 antibody could deepen and extend these anti-tumor responses.

Conclusions These data support continued clinical evaluation of SEA-CD40 in combination with chemotherapeutic agents and potentially in the future MMAE based ADCs. A phase 1 clinical trial is actively enrolling (NCT02376699) and includes a cohort in pancreatic cancer assessing the combination of SEA-CD40, gemcitabine, nab-paclitaxel, and pembrolizumab.

Ethics Approval Studies with human samples were performed according to institutional ethics standards. Animals studies were approved by and conducted in accordance with Seattle Genetics Institutional Care and Use Committee protocol #SGE-029.