A Monoclonal Antibody-GDNF Fusion Protein Is Not Neuroprotective and Is Associated with Proliferative Pancreatic Lesions in Parkinsonian Monkeys

Abstract

Glial cell line derived neurotrophic factor (GDNF) is a neurotrophic factor that has neuroprotective effects in animal models of Parkinson’s disease (PD) and has been proposed as a PD therapy. GDNF does not cross the blood brain barrier (BBB), and requires direct intracerebral delivery to be effective. Trojan horse technology, in which GDNF is coupled to a monoclonal antibody (mAb) against the human insulin receptor (HIR), has been proposed to allow GDNF BBB transport (ArmaGen Technologies Inc.). In this study we tested the feasibility of HIRMAb-GDNF to induce neuroprotection in parkinsonian monkeys, as well as its tolerability and safety. Adult rhesus macaques were assessed throughout the study with a clinical rating scale, a computerized fine motor skills task and general health evaluations. Following baseline measurements, the animals received a unilateral intracarotid artery MPTP injection. Seven days later the animals were evaluated, matched according to disability and blindly assigned to receive twice a week iv. treatments (vehicle, 1 or 5 mg/kg HIRmAb-GDNF) for a period of three months. HIRmAb-GDNF did not improve parkinsonian motor symptoms and induced a dose-dependent hypersensitivity reaction. Quantification of dopaminergic striatal optical density and stereological nigral cell counts did not demonstrate differences between treatment groups. Focal pancreatic acinar to ductular metaplasia (ADM) was noted in four of seven animals treated with 1 mg/kg HIRmAb-GDNF; two of four with ADM also had focal pancreatic intraepithelial neoplasia 1B (PanIN-1B) lesions. Minimal to mild, focal to multifocal, nonsuppurative myocarditis was noted in all animals in the 5 mg/kg treatment group. Our results demonstrate that HIRmAb-GDNF dosing in a monkey model of PD is not an effective neuroprotective strategy and may present serious health risks that should be considered when planning future use of the IR antibody as a carrier, or of any systemic treatment of a GDNF-containing molecule.

Developing Therapeutic Antibodies for Neurodegenerative Disease

“…For instance, the TfR antibodies utilized for in vivo validation of the anti-TfR/BACE1 bispecific does not compete with transferrin binding, and thus are not expected to alter iron transport and normal TfR function [123]. In the case of InsR a recent publication has shown severe safety observations in monkeys that may be related to InsR [141]. In general, it will be necessary to validate each new BBB target not only for its brain uptake potential, but also for the safety liabilities they may bring, including the need for extensive testing in higher species.…”

A gateway to the brain: shuttles for brain delivery of macromolecules

“…This did not improve Parkinsonian symptoms, but induced a dose-dependent hypersensitivity reaction, characterized with skin flushes, eyelid edema, vomiting, urticaria and in some cases respiratory distress; minimal to mild nonsuppurative myocarditis was noted in majority of animals [10]. Circulating antibodies against the HIRmAb-GDNF have been detected in all treated animals [10]. Serious health risks were also identified in the form of focal pancreatic metaplasia likely caused by proliferative actions of GDNF targeted to IR in pancreatic tissues [10].…”

“…Animals received twice weekly intravenous treatments of HIRmAb-GDNF for a period of 3 months. This did not improve Parkinsonian symptoms, but induced a dose-dependent hypersensitivity reaction, characterized with skin flushes, eyelid edema, vomiting, urticaria and in some cases respiratory distress; minimal to mild nonsuppurative myocarditis was noted in majority of animals [10]. Circulating antibodies against the HIRmAb-GDNF have been detected in all treated animals [10].…”

“…In the first example, the GDNF fused to a humanized antibody against IR (HIRMab), has been evaluated in Parkinsonian (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced) adult rhesus macaques [10]. Animals received twice weekly intravenous treatments of HIRmAb-GDNF for a period of 3 months.…”

“…Circulating antibodies against the HIRmAb-GDNF have been detected in all treated animals [10]. Serious health risks were also identified in the form of focal pancreatic metaplasia likely caused by proliferative actions of GDNF targeted to IR in pancreatic tissues [10].…”