The Role of Anti-Nerve Growth Factor Monoclonal Antibodies in the Control of Chronic Cancer and Non-Cancer Pain

Figures & data

Table 1 Summary of In Vivo Studies on the Role of Anti-NGF in Animal Models of Chronic Pain

Type of Study	Model	Type of Blocker	Dose	Effects and Adverse Effects	Reference
Pain assessment	Mouse model of DMM	TrkAd5	2 mg/kg either the day before surgery or 16 weeks after surgery (s.c.)	Reversion of the weight-bearing after treatment with TrkAd5 at 3 days and 16 weeks after surgery. Adverse effects were not evaluated	McNamee 2010^Citation19
Pain assessment	Rat model of MIA	Small molecule inhibitor of TrkA	Injection on day 7 after MIA induction (i.a.)	Reversion of the weight-bearing asymmetry of rats with MIA after 7 days from TrkAd5 inhibitor treatment. Adverse effects were not evaluated	Flannery 2015^Citation20
Pain assessment	Rat model of MIA	Anti-NGF mAb	9 mg/kg, 2 days after MIA induction (s.c.)	Reversion of the rat MIA model burrowing deficit after 3 days from mAb treatment. Adverse effects were not evaluated	Bryden 2015^Citation21
Pain and joint assessment	Rat model of OA	Anti-NGF mAb AS2886401-00	0.3 or 1 mg/kg on day 3 (i.v.)	Anti-NGF mAb exerted a long-lasting analgesic effect on pain during motion in a rat model of OA. AS2886401-00 did not suppress either edema or lesion of joint	Ishikawa 2015^Citation22
Veterinary pilot study	Dogs with degenerative joint disease	Canine-specific anti-NGF mAb	Single dose of 200 μg/kg of a 2 mg/mL solution (i.v.)	Alleviation of pain and mobility improvement in treated dogs with degenerative joint disease. Adverse effects were not evaluated	Lascelles 2015^Citation23
Pain behavior	PKCδ null mice subjected to DMM surgery	Anti-NGF mAb	30 μg (i.a.) given twice weekly from week 2 to week 8 post-DMM surgery	Treatment reduced mechanical allodynia of the hind paw from week 3 to week 8. Adverse effects were not evaluated	Kc 2016^Citation24
Pain and joint assessment	Rat MIA or rat MNX model	Active inhibitor of TrkA kinase activity	30 mg/kg (o.g.)	In the MIA model, treatment provoked a significant reduction in histological synovitis score and a trend toward a decrease in macroscopic chondropathy, histological cartilage degeneration, and subchondral bone scores by day 21. In the MNX model, treatment caused no effect on macroscopic chondropathy or histological cartilage degeneration scores, but a trend toward decreased knee swelling and increased histological subchondral bone score by day 2	Nwosu 2016^Citation25
Pain and joint assessment	Rat model (MMT)	Humanized anti-NGF mAb (tanezumab)	Preventive (0.1, 1, or 10 mg/kg, s.c., weekly from day of surgery through day 28 after surgery)	Tanezumab treatment led to increased tibial cartilage degeneration at days 7, 14, and 28. Increased tibial osteophytes by day 28 for all doses	LaBranche 2017^Citation26
Pain and joint assessment	Rat model of MIA	Anti-NGF mAb muMab 911	10 mg/kg (s.c.), weekly from the day of MIA induction	Anti-NGF mAb treatment attenuated OA pain behavior. Increased cartilage damage, subchondral bone sclerosis, and tibial osteophytes were detected in treated mice	Xu 2016^Citation27
Pain and joint assessment	C3H/HeJ mouse model of	Anti-NGF mAb (mAb911) at a dose of 10 mg/kg	10 mg/kg (i.p.)	Treatment with anti-NGF mAb increased spontaneous day/night activity and rearing in mice with acute post-orthopedic surgery pain	Majuta 2017^Citation28
Pain and joint assessment	C57BR/J mouse model of MIA	Anti-NGF mAb	10 mg/kg (i.p.)	Anti-NGF mAb suppressed the impairment of gait and upregulated CGRP in DRG neurons. These finding suggest that anti-NGF therapy might be valuable in the treatment of OA pain in the knee	Miyagi 2017^Citation29
Pain behavior	Surgicallyinduced murine OA model	CuMVttNGF vaccine		NGF vaccine strategy alleviated spontaneous pain behavior in surgically induced murine OA. Adverse effects were not evaluated	von Loga 2018^Citation30

Abbreviations: NGF, nerve growth factor; DMM, destabilization of the medial meniscus; TrkA, tropomyosin receptor kinase A receptor; s.c., subcutaneous; MIA, mono-iodoacetate; i.a., intra-articular; mAb, monoclonal antibody; OA, osteoarthritis; i.v., intravenous; PKCδ, protein kinase Cδ; MNX, medial meniscal tear; o.g., oral gavage; i.p., intra-peritoneal; CGRP, calcitonin gene-related peptide; DRG, dorsal root ganglia.

McNamee KE, Burleigh A, Gompels LL, et al. Treatment of murine osteoarthritis with TrkAd5 reveals a pivotal role for nerve growth factor in non-inflammatory joint pain. Pain. 2010;149(2):386–392. doi:10.1016/j.pain.2010.03.002

 Web of Science ®Google Scholar

Flannery CR, Moran N, Blasioli D, et al. Efficacy of a novel, locally delivered TrkA inhibitor in preclinical models of OA and joint pain. Osteoarthritis Cartilage. 2015;23(Supplement 2):A26–81. doi:10.1016/j.joca.2015.02.100

 Web of Science ®Google Scholar

Bryden LA, Nicholson JR, Doods H, Pekcec A. Deficits in spontaneous burrowing behavior in the rat bilateral monosodium iodoacetate model of osteoarthritis: an objective measure of pain-related behavior and analgesic efficacy. Osteoarthritis Cartilage. 2015;23(9):1605–1612. doi:10.1016/j.joca.2015.05.001

 Web of Science ®Google Scholar

Ishikawa G, Koya Y, Tanaka H, Nagakura Y. Long-term analgesic effect of a single dose of anti-NGF antibody on pain during motion without notable suppression of joint edema and lesion in a rat model of osteoarthritis. Osteoarthritis Cartilage. 2015;23(6):925–932. doi:10.1016/j.joca.2015.02.002

 PubMed Web of Science ®Google Scholar

Lascelles BD, Knazovicky D, Case B, et al. A canine-specific anti-nerve growth factor antibody alleviates pain and improves mobility and function in dogs with degenerative joint disease-associated pain. BMC Vet Res. 2015;30(11):101. doi:10.1186/s12917-015-0413-x

 Web of Science ®Google Scholar

Kc R, Li X, Kroin JS, et al. PKCδ null mutations in a mouse model of osteoarthritis alter osteoarthritic pain independently of joint pathology by augmenting NGF/TrkA-induced axonal outgrowth. Ann Rheum Dis. 2016;75(12):2133–2141. doi:10.1136/annrheumdis-2015-208444

 PubMed Web of Science ®Google Scholar

Nwosu LN, Mapp PI, Chapman V, Walsh DA. Blocking the tropomyosin receptor kinase A (TrkA) receptor inhibits pain behaviour in two rat models of osteoarthritis. Ann Rheum Dis. 2016;75(6):1246–1254. doi:10.1136/annrheumdis-2014-207203

 PubMed Web of Science ®Google Scholar

LaBranche TP, Bendele AM, Omura BC, et al. Nerve growth factor inhibition with tanezumab influences weight-bearing and subsequent cartilage damage in the rat medial meniscal tear model. Ann Rheum Dis. 2017;76(1):295–302. doi:10.1136/annrheumdis-2015-208913

 PubMed Web of Science ®Google Scholar

Xu L, Nwosu LN, Burston JJ, et al. The anti-NGF antibody muMab 911 both prevents and reverses pain behaviour and subchondral osteoclast numbers in a rat model of osteoarthritis pain. Osteoarthritis Cartilage. 2016;24(9):1587–1595. doi:10.1016/j.joca.2016.05.015

 PubMed Web of Science ®Google Scholar

Majuta LA, Guedon JG, Mitchell SAT, Ossipov MH, Mantyh PW. Anti-nerve growth factor therapy increases spontaneous day/night activity in mice with orthopedic surgery-induced pain. Pain. 2017;158(4):605–617. doi:10.1097/j.pain.0000000000000799

 PubMed Web of Science ®Google Scholar

Miyagi M, Ishikawa T, Kamoda H, et al. Efficacy of nerve growth factor antibody in a knee osteoarthritis pain model in mice. BMC Musculoskelet Disord. 2017;18(1):428. doi:10.1186/s12891-017-1792-x

 Web of Science ®Google Scholar

von Loga IS, El-Turabi A, Jostins L, et al. Active immunisation targeting nerve growth factor attenuates chronic pain behaviour in murine osteoarthritis. Ann Rheum Dis. 2019;78(5):672–675. doi:10.1136/annrheumdis-2018-214489

 Web of Science ®Google Scholar