Inhibition of costimulation allows for repeated systemic administration of adenoviral vector in rhesus monkeys

Abstract

Immunogenicity of recombinant adenoviral (Ad) vectors severely hampers the clinical development of gene therapy protocols using repeated vector administrations. Inhibition of costimulation by APCs was explored as a strategy to circumvent the immune response against Ad particles. This strategy was tested in rhesus monkeys, treated transiently with chimeric anti-human CD40 and anti-human CD86 antagonist monoclonal antibodies (MAbs) at the time of systemic administration of a recombinant Ad vector. After Ad vector administration in the absence of immunosuppressive treatment, transgene expression in the serum lasted about 3-4 weeks. All control animals developed a strong neutralizing antibody (NAb) response to the Ad particles, which totally prevented efficient administration of a second vector, as shown by the lack of transgene expression. Treatment with anti-CD40 and anti-CD86 chimeric MAbs delayed or blocked the development of a humoral response against Ad and the infiltration of CD8 þ lymphocytes into the liver. This resulted in (i) increased persistence of Ad-transduced cells after injection of a first vector encoding a nonimmunogenic transgene, and (ii) the possibility of readministering a second Ad vector with significant efficacy. In both respects, the combined blockade of CD40 and CD86 was more efficient than treatment with anti-CD40 alone. This study shows for the first time in non-human primates that blocking CD40 and CD86 costimulatory molecules represents a promising strategy to inhibit immune responses against an Ad vector injected systemically.

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.…”

“…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).…”

Merck Ad5/HIV induces broad innate immune activation that predicts CD8 + T-cell responses but is attenuated by preexisting Ad5 immunity

“…3D and Dataset S1, tab 13). Our results are compatible with the suggestion that Ad5 nAb may effectively lower the dose of the vaccine detected by the innate immune system (8,46) and are consistent with the reduced vaccine immunogenicity seen in vaccine recipients with nAb titers >200 (3). Our results are also compatible with a model in which nAbs negatively regulate innate signaling pathways.…”

Safety and tolerability of antagonist anti‐human CD40 Mab ch5D12 in patients with moderate to severe Crohn's disease

“…The non-stimulatory antagonistic activity of Mab 5D12 (anti-human CD40) was demonstrated in various in vitro studies using different CD40-bearing cell types [20][21][22] and ch5D12 antagonist activity was validated in vivo using various non-human primate disease models. [23][24][25][26][27] Chimeric 5D12 (ch5D12) is a molecularly engineered human IgG 4 antibody containing the variable domains of the heavy and light chains of 5D12 and was constructed to reduce the potential for immunogenicity and to enhance the in vivo half-life of the 5D12 Mab when used in humans.…”