Bispecific antibodies increase the therapeutic window of CD40 agonists through selective dendritic cell targeting.

Therapeutic use of agonistic anti-CD40 antibodies is a potentially powerful approach for activation of the immune response to eradicate tumors. However, the translation of this approach to clinical practice has been substantially restricted due to the severe dose-limiting toxicities observed in multiple clinical trials. Here, we demonstrate that conventional type 1 dendritic cells are essential for triggering antitumor immunity but not the toxicity of CD40 agonists, while macrophages, platelets and monocytes lead to toxic events. Therefore, we designed bispecific antibodies that target CD40 activation preferentially to dendritic cells, by coupling the CD40 agonist arm with CD11c-, DEC-205- or CLEC9A-targeting arms. These bispecific reagents demonstrate a superior safety profile compared to their parental CD40 monospecific antibody while triggering potent antitumor activity. We suggest such cell-selective bispecific agonistic antibodies as a drug platform to bypass the dose-limiting toxicities of anti-CD40, and of additional types of agonistic antibodies used for cancer immunotherapy.

Zonation of Pancreatic Acinar Cells in Diabetic Mice.

The islets of Langerhans are dynamic structures that can change in size, number of cells, and molecular function in response to physiological and pathological stress. Molecular cues originating from the surrounding "peri-islet" acinar cells that could facilitate this plasticity have not been explored. Here, we combine single-molecule transcript imaging in the intact pancreas and transcriptomics to identify spatial heterogeneity of acinar cell gene expression. We find that peri-islet acinar cells exhibit a distinct molecular signature in db/db diabetic mice that includes upregulation of trypsin family genes and elevated mTOR activity. This zonated expression program seems to be induced by CCK that is secreted from islet cells. Elevated peri-islet trypsin secretion could facilitate the islet expansion observed in this model via modulation of the islet capsule matrix components. Our study highlights a molecular axis of communication between the pancreatic exocrine and endocrine compartments that may be relevant to islet expansion.