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Published on: April 22, 2010
Preclinical assessment of anti-CD40 Mab 5D12 in cynomolgus monkeys
Louis Boon1, Jon D Laman, Antonio Ortiz-Buijsse
1Tanox Pharma B.V., Sandinostraat 9, 1069 NJ, Amsterdam, The Netherlands.
Abstract:
Monoclonal antibody (Mab) 5D12 is a potent antagonist of the CD40-CD40L pathway. This cellular interaction has been validated in a large number of experimental animal models where dys-regulation of the immune system plays a role. Chimeric 5D12 (ch5D12) was constructed to reduce the potential immunogenicity and enhance the in vivo half-life when used in humans. ch5D12 is a molecularly engineered human IgG(4) antibody containing the variable domains of the heavy and light chains of the murine version of 5D12 (mu5D12). This new chimeric Mab was tested in a marmoset experimental autoimmune encephalomyelitis model and was shown to effectively prevent disease symptoms. The results of this in vivo evaluation supported clinical use of ch5D12 for immune targeted diseases. Therefore GMP material was prepared and a GLP-compliant tissue cross-reactivity study on human tissues (3 donors/37 tissues) and cynomolgus tissues (2 donors/37 tissues) was performed. ch5D12 stained on the surface of B cells and selected dendritic cells and no unexpected cross-reactivity was observed. The identical staining patterns in human and cynomolgus tissues justified the use of cynomolgus monkeys as a relevant model for humans. A GLP-compliant safety and tolerability evaluation for ch5D12 in cynomolgus monkeys was performed using the GMP produced material. Weekly administration of ch5D12 at two dose levels for 4 weeks was shown to be safe and without any side effects in all monkeys.
Insights
Chimeric 5D12 (ch5D12) antibody effectively prevented autoimmune disease symptoms in marmosets. Safety and cross-reactivity studies in cynomolgus monkeys supported its clinical use for immune-targeted diseases.
Area of Science:
- Immunology
- Pharmacology
- Translational Medicine
Background:
- The CD40-CD40L pathway is crucial in immune system regulation and implicated in various diseases.
- Monoclonal antibody (Mab) 5D12, a CD40-CD40L antagonist, has shown efficacy in preclinical models.
- Chimeric 5D12 (ch5D12) was engineered to improve human therapeutic potential by reducing immunogenicity and extending half-life.
Purpose of the Study:
- To evaluate the efficacy of ch5D12 in a non-human primate model of autoimmune disease.
- To assess the tissue cross-reactivity of ch5D12 in human and cynomolgus monkey tissues.
- To determine the safety and tolerability of ch5D12 in cynomolgus monkeys.
Main Methods:
- ch5D12 efficacy was tested in a marmoset experimental autoimmune encephalomyelitis model.
- Good Laboratory Practice (GLP)-compliant tissue cross-reactivity studies were conducted on human and cynomolgus monkey tissues.
- GLP-compliant safety and tolerability studies involved weekly administration of ch5D12 to cynomolgus monkeys at two dose levels for four weeks.
Main Results:
- ch5D12 effectively prevented disease symptoms in the marmoset experimental autoimmune encephalomyelitis model.
- ch5D12 demonstrated specific binding to B cells and certain dendritic cells in both human and cynomolgus tissues, with no unexpected cross-reactivity.
- Weekly administration of ch5D12 for four weeks was found to be safe and well-tolerated in cynomolgus monkeys, with no observed side effects.
Conclusions:
- The efficacy in the marmoset model and favorable safety profile support the clinical use of ch5D12 for immune-targeted diseases.
- The observed identical staining patterns in human and cynomolgus tissues validate the use of cynomolgus monkeys as a relevant preclinical model.
- ch5D12 represents a promising therapeutic candidate for autoimmune and immune-mediated conditions.
