Prevention of Experimental Autoimmune Encephalomyelitis in the Common Marmoset (Callithrix jacchus) Using a Chimeric Antagonist Monoclonal Antibody Against Human CD40 Is Associated with Altered B Cell Responses

Abstract

Inhibition of CD40-CD40 ligand interaction is a potentially effective approach for treatment of autoimmune diseases, such as multiple sclerosis. We have investigated this concept with a chimeric antagonist anti-human CD40 mAb (ch5D12) in the marmoset monkey experimental autoimmune encephalomyelitis (EAE) model. Marmosets were immunized with recombinant human myelin oligodendrocyte glycoprotein (rMOG) and treated from the day before immunization (day −1) until day 50 with either ch5D12 (5 mg/kg every 2–4 days) or placebo. On day 41 after the induction of EAE, four of four placebo-treated monkeys had developed severe clinical EAE, whereas all animals from the ch5D12-treated group were completely free of disease symptoms. High serum levels of ch5D12 associated with complete coating of CD40 on circulating B cells were found. At necropsy placebo- and ch5D12-treated animals showed similar MOG-specific lymphoproliferative responses in vitro, but ch5D12 treatment resulted in strongly reduced anti-MOG IgM Ab responses and delayed anti-MOG IgG responses. Most importantly, treatment with ch5D12 prevented intramolecular spreading of epitope recognition. Postmortem magnetic resonance imaging and immunohistologic analysis of the CNS showed a markedly reduced lesion load after ch5D12 treatment. In conclusion, the strong reduction of clinical, pathological, and radiological aspects of EAE by ch5D12 treatment in this preclinical model points to a therapeutic potential of this engineered antagonist anti-CD40 mAb for multiple sclerosis.

Induction of an Altered CD40 Signaling Complex by an Antagonistic Human Monoclonal Antibody to CD40

“…The striking inability of PG102-mediated CD40 engagement to trigger early signaling pathways in immune cells is consistent with its reported inhibition of CD40-mediated B cell effector functions (10,11). This also correlates with PG102-mediated inhibition of in vivo CD40-dependent promotion of inflammation and transplant rejection in animal models (12)(13)(14) and early clinical human studies (15). In some regards, this PG102-induced altered CD40 signaling resembles the "alternative" signaling pathways that bacterial superantigens are reported to trigger when they bind TCR/MHC complexes (reviewed in Ref.…”

“…The antagonistic humanized anti-hCD40 mAb PG102 is a less immunogenic form of the humanized anti-hCD40 mAb ch5D12 (12) and was provided by Fast Forward Pharmaceuticals. The humanized anti-hCD40 control mAb 4D11 was used in Fig.…”

“…Subsequently, a chimeric form of 5D12 (ch5D12) containing human IgG4 constant regions was produced. The ch5D12 mAb prevents development of experimental autoimmune encephalomyelitis in marmosets (12), as well as prolongs the survival of kidney allografts and allows repeated systemic administration of adenoviral gene therapy vectors in rhesus monkeys (13,14). In an open-label dose-escalation phase I/IIa study of Crohn's disease patients, ch5D12 was well tolerated and showed promising clinical benefit (15).…”

Quantitative MRI‐pathology correlations of brain white matter lesions developing in a non‐human primate model of multiple sclerosis

“…This novel experimental model shows remarkable clinical and neuropathological similarity with MS (1,15). Therapies which have been beneficial in rodents are prophylactically (16,17) and therapeutically (6,7) confirmed in this model with MRI. However, it is unknown to what extent the histological changes occurring during lesions progression are reflected by MRI.…”

The common marmoset (<i>Callithrix jacchus</i>): a relevant preclinical model of human (auto)immune-mediated inflammatory disease of the brain

“…For this reason, a second experiment was performed testing a novel mouse-human chimeric version of 5D12 in the rhMOG/CFA model. Also in the mAbtreated monkeys clinical signs did not develop during the 40-day observation period, while all placebo-treated monkeys displayed clinical EAE (Boon et al, 2001). Importantly, the treatment effect was reflected by alteration of the antibody reactivity profile with a panel of rhMOG peptides.…”