Ex vivo assays of dendritic cell activation and cytokine profiles as predictors of in vivo effects in an anti-human CD40 monoclonal antibody ChiLob 7/4 phase I trial.
Immunostimulatory antibodies entering the clinic create challenge in terms of not only pharmacodynamics for monitoring anticipated mechanisms but also predetermining cytotoxicity. We show the use of ex vivo whole-blood samples to predict the activation requirements, cytokine signature, and adverse events of an anti-human-CD40 chimeric IgG1 antibody, ChiLob 7/4. Assessments were initially undertaken on human myeloid (mDC1) and plasmacytoid (pDC) dendritic cells, in which an absolute need for cross-linking was shown through the upregulation of activation markers CD83 and CCR7. Subsequent cytokine secretion evaluations of ex vivo whole blood showed the cross-linked antibody-induced increases in MIP1β, interleukin (IL)-8, IL-12, TNFα, and IL-6. This cytokine signature compared favorably with the Toll-like receptor (TLR) ligand lipopolysaccharide (LPS), in which levels of TNFα and IL-6 were significantly higher, suggesting a less intense proinflammatory response and possible modified cytokine release syndrome when used in human trials. Following first-in-human use of this agent within a dose escalation study, in vivo evaluations of dendritic cell activation and secreted cytokines closely matched the predetermined immunomonitoring endpoints. Patients showed a comparable pattern of MIP1β, IL-8, and IL-12 secretion, but no TNFα and IL-6 were identified. Mild symptoms relating to a cytokine release syndrome were seen at an equivalent dosage to that observed for dendritic cell activation and cytokine release. In summary, ChiLob 7/4 induces a distinctive pattern of dendritic cell activation and cytokine secretion in ex vivo assays that can be predictive of in vivo responses. Such preclinical approaches to monoclonal antibody evaluation may inform both the starting dosages and the anticipated cytokine release events that could occur, providing a valuable adjunct for future first-in-human assessments of immunostimulatory antibodies.
Authors' Affiliations: Southampton NIHR Experimental Cancer Medicine Centre, Southampton, United Kingdom.
F
F
Chowdhury
P W
PW
Johnson
M J
MJ
Glennie
A P
AP
Williams
D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D000938:Antigen-Presenting Cells / Q000187:drug effects; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D019013:CD40 Antigens / Q000037:antagonists & inhibitors*; D016207:Cytokines / Q000276:immunology*; D003713:Dendritic Cells / Q000187:drug effects*; D004334:Drug Administration Schedule; D006801:Humans; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D051193:Toll-Like Receptors / Q000276:immunology
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D019013:CD40 Antigens; D016207:Cytokines; D051193:Toll-Like Receptors