Immunotherapy for neuroblastoma elicits a complement dependent whole body allodynia
-
Linda S. Sorkin
GD2 ganglioside is found on plasma membranes of tumor cells of neuroectodermal origin, including neuroblastoma cells. A chimeric antibody against GD2 (ch14.18) is currently being used as a treatment for pediatric neuroblastoma. Intravenous administration of the antibody induces severe whole body allodynia in patients which lasts from 24 to 48 h. Similar administration of antibody to rats produces tactile, but not thermal sensitivity, whole body touch evoked agitation as well as ectopic activation of identified C nociceptors in the sural nerve. Both the peripheral nerve firing and patient allodynia are sensitive to low dose systemic lidocaine. Pain behavior, in rats and children, is also sensitive to gabapentin.
We postulated that the mechanism of the anti-GD2-induced pain involved activation of the complement cascade resulting in a complement-dependent cytotoxicity (CDC). With this in mind we engineered a new form of the antibody (Hu14.18) with a point mutation within the C region that was intended to reduce complement fixation. In vitro experiments of the mutated antibody confirmed significantly diminished CDC, however, there was still a strong antibody-dependent cellular cytotoxicity (ADCC) involving natural killer cells. In rats, Hu14.18 results in a smaller magnitude of mechanical sensitization with a greatly shortened duration compared to ch14.18. Thus, ability to activate complement increases the antibody-elicited pain.
The two most likely complement factors to be involved in this process are C5a and membrane attack complex (MAC). Systemic pretreatment with a C5a receptor antagonist totally prevented ch14.18 elicited pain behavior. To look at the role of MAC, we utilized rats with deficient complement factor C6 as C6 is a necessary component of membrane attack complex. C6 deficient rats injected with ch14.18 showed greatly reduced tactile sensitivity. Injection of these animals with Hu14.18 resulted in pain behavior that was no different from animals injected with saline. We conclude that both C5a and MAC are necessary for full manifestation of the anti-GD2 induced pain behavior, although C5a appears to be playing a greater role. Reducing complement activity of immunotherapeutic agents may increase their utility by decreasing their side effects.
© 2010 Scandinavian Association for the Study of Pain
Articles in the same Issue
- Editorial comment
- Functional brain imaging of acute postoperative pain
- Clinical pain research
- Brain activation due to postoperative pain from the right hand measured with regional cerebral blood flow using positron emission tomography
- Editorial comment
- Long-term low-dose transdermal buprenorphine therapy for chronic noncancer pain
- Original experimental
- A 6-months, randomised, placebo-controlled evaluation of efficacy and tolerability of a low-dose 7-day buprenorphine transdermal patch in osteoarthritis patients naïve to potent opioids
- Editorial comment
- Repeated nociceptive stimulation for detecting drug effects
- Original experimental
- The effects of gabapentin in human experimental pain models
- Editorial comment
- Whether the weather influences pain: High prevalence of chronic pain in Iceland and Norway: Common genes? Or lack of sunshine and vitamin D?
- Observational studies
- A population based study of the prevalence of pain in Iceland
- Editorial comment
- Swedish nurses are prone to chronic shoulder and back pain because of miserable working conditions and poor leadership?
- Observational studies
- Predicting of pain, disability, and sick leave regarding a non-clinical sample among Swedish nurses
- Abstracts
- Trigeminal neuralgia or odontogenic pain
- Abstracts
- What’s wrong with animal models of pain?
- Abstracts
- Immunotherapy for neuroblastoma elicits a complement dependent whole body allodynia
- Abstracts
- Pain mechanisms in animal models of rheumatoid arthritis
- Abstracts
- Translating basic research to pharmacological treatment of neuropathic pain
- Abstracts
- Free Poster Presentations: Forearm heat pain does not inhibit electrically induced tibialis anterior muscle pain
- Abstracts
- Offset analgesia evoked by non-contact thermal stimulator
- Abstracts
- Inhibition of FAAH reverses spinal LTP
- Abstracts
- Hyperexcitable C-nociceptors in human paroxysmal pain
- Abstracts
- Pain sensitivity and experimentally induced sensitization in red haired women
- Abstracts
- How are opioids used in Norway? Persistent use, utilization of depot formulation and age profile in non-palliation patients
- Abstracts
- To which extent does incident and persistent use of weak opioids predict problematic opioid use?
- Abstracts
- Is transdermal buprenorphine for chronic non-malignant pain used long term without co-medication with other potentially addictive drugs?
- Abstracts
- Prostaglandin E2 production in synovial tissue and acute postoperative pain after knee arthroscopy
- Abstracts
- Girl presenting with oesophageal spasm pain after fundoplication
- Abstracts
- Epidemiology of persistent postoperative pain: Association of persistent pain and sensory abnormalities
- Abstracts
- Cost–benefit of a 13-week multidiciplinary rehabilitation course for chronic non-malignant pain patients
- Abstracts
- A novel and effective treatment modality for medically unexplained pain
- Abstracts
- Somatocognitive therapy in the management of chronic gynaecological pain. A review of current approach and historical background
- Abstract
- The Manual Intervention Trial (MINT)—The effect of various combinations of naprapathic manual therapy. The study protocol of a randomized controlled trial
- Abstracts
- The experience of chronic pain, loss and grief
- Abstracts
- Effect of buprenorphine and fentanyl in experimental induced superficial, deep and hyperalgesic pain
- Abstract
- Pretreatment with opioids enhances afferent induced long-term potentiation in the rat dorsal horn
- Abstracts
- Pigs in pain—Porcine behavioural responses towards mechanical nociceptive stimulation directed at the hind legs
- Abstracts
- A human experimental bone pain model
Articles in the same Issue
- Editorial comment
- Functional brain imaging of acute postoperative pain
- Clinical pain research
- Brain activation due to postoperative pain from the right hand measured with regional cerebral blood flow using positron emission tomography
- Editorial comment
- Long-term low-dose transdermal buprenorphine therapy for chronic noncancer pain
- Original experimental
- A 6-months, randomised, placebo-controlled evaluation of efficacy and tolerability of a low-dose 7-day buprenorphine transdermal patch in osteoarthritis patients naïve to potent opioids
- Editorial comment
- Repeated nociceptive stimulation for detecting drug effects
- Original experimental
- The effects of gabapentin in human experimental pain models
- Editorial comment
- Whether the weather influences pain: High prevalence of chronic pain in Iceland and Norway: Common genes? Or lack of sunshine and vitamin D?
- Observational studies
- A population based study of the prevalence of pain in Iceland
- Editorial comment
- Swedish nurses are prone to chronic shoulder and back pain because of miserable working conditions and poor leadership?
- Observational studies
- Predicting of pain, disability, and sick leave regarding a non-clinical sample among Swedish nurses
- Abstracts
- Trigeminal neuralgia or odontogenic pain
- Abstracts
- What’s wrong with animal models of pain?
- Abstracts
- Immunotherapy for neuroblastoma elicits a complement dependent whole body allodynia
- Abstracts
- Pain mechanisms in animal models of rheumatoid arthritis
- Abstracts
- Translating basic research to pharmacological treatment of neuropathic pain
- Abstracts
- Free Poster Presentations: Forearm heat pain does not inhibit electrically induced tibialis anterior muscle pain
- Abstracts
- Offset analgesia evoked by non-contact thermal stimulator
- Abstracts
- Inhibition of FAAH reverses spinal LTP
- Abstracts
- Hyperexcitable C-nociceptors in human paroxysmal pain
- Abstracts
- Pain sensitivity and experimentally induced sensitization in red haired women
- Abstracts
- How are opioids used in Norway? Persistent use, utilization of depot formulation and age profile in non-palliation patients
- Abstracts
- To which extent does incident and persistent use of weak opioids predict problematic opioid use?
- Abstracts
- Is transdermal buprenorphine for chronic non-malignant pain used long term without co-medication with other potentially addictive drugs?
- Abstracts
- Prostaglandin E2 production in synovial tissue and acute postoperative pain after knee arthroscopy
- Abstracts
- Girl presenting with oesophageal spasm pain after fundoplication
- Abstracts
- Epidemiology of persistent postoperative pain: Association of persistent pain and sensory abnormalities
- Abstracts
- Cost–benefit of a 13-week multidiciplinary rehabilitation course for chronic non-malignant pain patients
- Abstracts
- A novel and effective treatment modality for medically unexplained pain
- Abstracts
- Somatocognitive therapy in the management of chronic gynaecological pain. A review of current approach and historical background
- Abstract
- The Manual Intervention Trial (MINT)—The effect of various combinations of naprapathic manual therapy. The study protocol of a randomized controlled trial
- Abstracts
- The experience of chronic pain, loss and grief
- Abstracts
- Effect of buprenorphine and fentanyl in experimental induced superficial, deep and hyperalgesic pain
- Abstract
- Pretreatment with opioids enhances afferent induced long-term potentiation in the rat dorsal horn
- Abstracts
- Pigs in pain—Porcine behavioural responses towards mechanical nociceptive stimulation directed at the hind legs
- Abstracts
- A human experimental bone pain model
