Anti-GD2 with an FC point mutation reduces complement fixation and decreases antibody-induced allodynia
- 1 April 2010
- journal article
- Published by Ovid Technologies (Wolters Kluwer Health) in Pain
- Vol. 149 (1), 135-142
- https://doi.org/10.1016/j.pain.2010.01.024
Abstract
Monoclonal antibodies against GD2 ganglioside, such as ch14.18, the human–mouse chimeric antibody, have been shown to be effective for the treatment of neuroblastoma. However, treatment is associated with generalized, relatively opiate-resistant pain. We investigated if a point mutation in ch14.18 antibody (hu14.18K332A) to limit complement-dependent cytotoxicity (CDC) would ameliorate the pain behavior, while preserving antibody-dependent cellular cytotoxicity (ADCC). In vitro, CDC and ADCC were measured using europium-TDA assay. In vivo, allodynia was evaluated by measuring thresholds to von Frey filaments applied to the hindpaws after injection of either ch14.18 or hu14.18K332 into wild type rats or rats with deficient complement factor 6. Other rats were pretreated with complement factor C5a receptor antagonist and tested following ch14.18 injection. The mutation reduces the antibody's ability to activate complement, while maintaining its ADCC capabilities. Injection of hu14.18K322 (1 or 3 mg/kg) produced faster resolving allodynia than that engendered by ch14.18 (1 mg/kg). Injection of ch14.18 (1 mg/kg) into rats with C6 complement deficiency further reduced antibody-induced allodynia, while pre-treatment with complement factor C5a receptor antagonist completely abolished ch14.18-induced allodynia. These findings showed that mutant hu14.18 K322 elicited less allodynia than ch14.18 and that ch14.18-elicited allodynia is due to activation of the complement cascade: in part, to formation of membrane attack complex, but more importantly to release of complement factor C5a. Development of immunotherapeutic agents with decreased complement-dependent lysis while maintaining cellular cytotoxicity may offer treatment options with reduced adverse side effects, thereby allowing dose escalation of therapeutic antibodies.Keywords
This publication has 38 references indexed in Scilit:
- Quality of Surveillance for Stage I Testis Cancer in the CommunityJournal of Clinical Oncology, 2009
- Complement activation in the peripheral nervous system following the spinal nerve ligation model of neuropathic pain ☆Pain, 2008
- Complement activation contributes to leukocyte recruitment and neuropathic pain following peripheral nerve injury in ratsEuropean Journal of Neuroscience, 2007
- Complement Induction in Spinal Cord Microglia Results in Anaphylatoxin C5a-Mediated Pain HypersensitivityJournal of Neuroscience, 2007
- JNK1 activation mediates C5b-9-induced P0 mRNA instability and P0 gene expression in Schwann cellsJournal of the Peripheral Nervous System, 2006
- Gabapentin Reverses the Allodynia Produced by the Administration of Anti-GD2 Ganglioside, an Immunotherapeutic DrugAnesthesia & Analgesia, 1998
- Electrophysiological characteristics of primary afferent fibers after systemic administration of anti-GD2 ganglioside antibodyPain, 1997
- Gangliosides and allied glycosphingolipids in human peripheral nerve and spinal cordBiochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism, 1994
- A phase I study of neuroblastoma with the anti-ganglioside GD2 antibody 14.G2aCancer Immunology, Immunotherapy, 1992
- Efficient Analysis of Experimental ObservationsAnnual Review of Pharmacology and Toxicology, 1980