Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 2 de 2
Filter
Add more filters










Database
Language
Publication year range
1.
Neurobiol Dis ; 159: 105492, 2021 11.
Article in English | MEDLINE | ID: mdl-34478849

ABSTRACT

Repulsive guidance molecule A (RGMa) is a potent inhibitor of axonal growth and a regulator of neuronal cell death. It is up-regulated following neuronal injury and accumulates in chronic neurodegenerative diseases. Neutralizing RGMa has the potential to promote neuroregeneration and neuroprotection. Previously we reported that a rat anti-N terminal RGMa (N-RGMa) antibody r5F9 and its humanized version h5F9 (ABT-207) promote neuroprotection and neuroregeneration in preclinical neurodegenerative disease models. However, due to its cross-reactivity to RGMc/hemojuvelin, ABT-207 causes iron accumulation in vivo, which could present a safety liability. Here we report the generation and characterization of a novel RGMa-selective anti-N-RGMa antibody elezanumab, which is currently under Phase 2 clinical evaluation in multiple disease indications. Elezanumab, a human monoclonal antibody generated by in vitro PROfusion mRNA display technology, competes with ABT-207 in binding to N-RGMa but lacks RGMc cross-reactivity with no impact on iron metabolism. It neutralizes repulsive activity of soluble RGMa in vitro and blocks membrane RGMa mediated BMP signaling. In the optic nerve crush and optic neuritis models, elezanumab promotes axonal regeneration and prevents retinal nerve fiber layer degeneration. In the spinal targeted experimental autoimmune encephalomyelitis (EAE) model, elezanumab promotes axonal regeneration and remyelination, decreases inflammatory lesion area and improves functional recovery. Finally, in the mouse cuprizone model, elezanumab reduces demyelination, which is consistent with its inhibitory effect on BMP signaling. Taken together, these preclinical data demonstrate that elezanumab has neuroregenerative and neuroprotective activities without impact on iron metabolism, thus providing a compelling rationale for its clinical development in neurodegenerative diseases.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental , GPI-Linked Proteins , Nerve Regeneration , Nerve Tissue Proteins , Neuroprotection , Optic Nerve Injuries , Optic Nerve , Optic Neuritis , Recovery of Function , Retina , Animals , Mice , Cuprizone/toxicity , Encephalomyelitis, Autoimmune, Experimental/chemically induced , Encephalomyelitis, Autoimmune, Experimental/physiopathology , GPI-Linked Proteins/antagonists & inhibitors , Monoamine Oxidase Inhibitors/toxicity , Nerve Regeneration/drug effects , Nerve Regeneration/physiology , Nerve Tissue Proteins/antagonists & inhibitors , Neuroprotection/drug effects , Optic Nerve/drug effects , Optic Nerve/physiology , Optic Nerve Injuries/physiopathology , Optic Neuritis/physiopathology , Recovery of Function/drug effects , Recovery of Function/physiology , Retina/drug effects , Surface Plasmon Resonance
2.
Protein Eng Des Sel ; 28(10): 427-35, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26337062

ABSTRACT

Since the invention of phage display, in vitro antibody display technologies have revolutionized the field of antibody discovery. In combination with antibody libraries constructed with sequences of human origin, such technologies enable accelerated therapeutic antibody discovery while bypassing the laborious animal immunization and hybridoma generation processes. Many in vitro display technologies developed since aim to differentiate from phage display by displaying full-length IgG proteins, utilizing eukaryotic translation system and codons, increasing library size or real-time kinetic selection by fluorescent activated cell sorting. We report here the development of an mRNA display technology and an accompanying HCDR3 size spectratyping monitor for human antibody discovery. Importantly, the mRNA display technology maintains a monovalent linkage between the mRNA (genotype) and display binding protein (phenotype), which minimizes avidity effect common in other display systems and allows for a stringent affinity and off-rate selection. The mRNA display technology successfully identified 100 human antibodies in 15 different selections against various targets from naïve human antibody libraries. These antibodies in general have high affinity and diversity. By analyzing the germline usage and combination of antibodies selected by the mRNA display technology, we identified trends and determined the productivity of each germline subgroup in the libraries that could serve as the knowledge base for constructing fully synthetic, next generation antibody libraries.


Subject(s)
Cell Surface Display Techniques/methods , Single-Domain Antibodies/genetics , Humans , RNA, Messenger/genetics
SELECTION OF CITATIONS
SEARCH DETAIL
...