Preclinical assessment of anti-CD40 Mab 5D12 in cynomolgus monkeys

Boon, Louis; Laman, Jon D.; Ortiz-Buijsse, Antonio; Hartog, Marcel T. den; Hoffenberg, Simon; Liu, Patrick; Shiau, Fred; Boer, Mark de

doi:10.1016/s0300-483x(02)00057-4

Cited by 35 publications

(36 citation statements)

References 33 publications

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“…Several amino acids in both H and L chains of the ch5D12 mAb were subsequently changed to remove potential MHC-binding epitopes and thus reduce possible immunogenicity (M. de Boer, personal communication); the resultant mAb is PG102. Previous studies showed that ch5D12 inhibits CD40-induced production of proinflammatory cytokines (16), and we observed this as well with PG102 in B cell cultures (K.L. Oxley and G.A.…”

supporting

confidence: 85%

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

Bankert

Oxley

Smith

et al. 2015

The Journal of Immunology

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Blocking the interaction of CD40 with its ligand CD154 is a desirable goal of therapies for preventing and/or ameliorating autoimmune diseases and transplant rejection. CD154-blocking mAbs used in human clinical trials resulted in unanticipated vascular complications, leading to heightened interest in the therapeutic potential of antagonist mAbs specific for human CD40. Abs that do not require physical competition with CD154 to inhibit CD40 signaling have particular therapeutic promise. In this study, we demonstrate that the antagonist anti-human CD40 mAb PG102 fails to trigger CD40-mediated activation, as well as impairs CD154-mediated CD40 activation, via a distinct nonstimulatory CD40 signaling mechanism. PG102 did not induce early CD40-induced signaling events, and it inhibited early kinase and transcription factor activation by CD154 or agonist anti-CD40 mAbs. However, PG102 stimulated normal CD40-mediated TNFR-associated factor (TRAF)2 and TRAF3 degradation. PG102 induced the formation of a CD40 signaling complex that contained decreased amounts of both TRAF2 and TRAF3 and TRAF2-associated signaling proteins. Additionally, PG102-induced CD40 signaling complexes failed to recruit TRAF6 to detergent-insoluble membrane fractions. Fab fragments of PG102, while retaining CD40 binding, did not induce TRAF degradation, nor could they inhibit CD154-stimulated B cell signaling, indicating that CD40 aggregation is required for the signaling inhibition induced by PG102. The antagonistic impact of PG102 on CD40 signaling reveals that the manner of CD40 ligation can determine sharply different outcomes for CD40 signaling and suggests that such information can be used to therapeutically manipulate these outcomes.

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supporting

confidence: 85%

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

Bankert

Oxley

Smith

et al. 2015

The Journal of Immunology

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“…The new therapeutic ch5D12 was generated to increase the serum half-life of the mAb and to reduce its potential immunogenicity in humans (11). However, it was observed in this study that the serum half-life of ch5D12 was unexpectedly low and was only slightly improved compared with that of mu5D12 in marmoset monkeys.…”

Section: Discussioncontrasting

confidence: 45%

“…5D12 strongly inhibits Ab production (both IgM and IgG) by human B cells cocultured with activated CD40L ϩ human T cells (9) as well as production of IL-12 and TNF-␣ by human monocytes induced by CD40L-CD40 interaction and IFN-␥ (10). To reduce the potential immunogenicity and enhance the in vivo half-life of the parent 5D12 mAb for administration in humans, the murine parent Ab was re-engineered as a chimeric mouse-human mAb with a human IgG4 constant region (11).…”

mentioning

confidence: 99%

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

Boon¹,

Brok

Bauer

et al. 2001

The Journal of Immunology

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114

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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.

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“…This MAb, either in its chimeric form (ch5D12) 24 or as parent murine MAb (mu5D12) 25 was shown to successfully protect from EAE in a non-human primate model, and proved to be safe in cynomolgus monkeys. 26 The anti-human CD86 MAb Fun-1 has not been widely used in non-human primate animal models. However, the efficacy of this MAb in combination with anti-human CD40 has been shown recently in a rhesus monkey kidney transplantation study.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2004

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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.

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Preclinical assessment of anti-CD40 Mab 5D12 in cynomolgus monkeys

Cited by 35 publications

References 33 publications

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

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

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

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

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