Agonistic antibodies to trkc receptors and uses thereof

Abstract

There are provided herein novel monoclonal antibodies that selectively bind and/or activate TrkC receptors, pharmaceutical compositions thereof and the use thereof for treating or preventing conditions which require activation of TrkC, such as amyotrophic lateral sclerosis and other neurodegenerative conditions and motor neuron diseases. The monoclonal antibodies are useful to screen for agents that share the same binding epitope on the TrkC receptor.

1 - 41 . (canceled) 
     
     
         42 . A dosage form comprising
 a monoclonal antibody or a fragment, portion, variant or derivative thereof, wherein said monoclonal antibody, fragment, portion, variant or derivative thereof, specifically binds to the juxtamembrane region, a peptide within the juxtamembrane region, or a peptide having the amino acid sequence ESTDNFILFDEVSPTPPI (SEQ ID NO: 1), of TrkC; and   an excipient or a carrier.   
     
     
         43 . The dosage form of  claim 42 , wherein said monoclonal antibody or said fragment, portion, variant or derivative thereof, modulates TrkC. 
     
     
         44 . The dosage form of  claim 42 , wherein said monoclonal antibody or said fragment, portion, variant or derivative thereof, does not bind and/or modulate TrkA, TrkB, p75NTR or a combination thereof. 
     
     
         45 . The dosage form of  claim 42 , wherein said monoclonal antibody or said fragment, portion, variant or derivative thereof, binds TrkC differently from NT-3. 
     
     
         46 . The dosage form of  claim 42 , wherein said monoclonal antibody or said fragment, portion, variant or derivative thereof, binds an epitope of human TrkC with a sequence comprising the juxtamembrane region or a portion thereof of human TrkC. 
     
     
         47 . The dosage form of  claim 42 , wherein said monoclonal antibody or said fragment, portion, variant or derivative thereof, comprises all of the six CDRs from a monoclonal antibody produced by a hybridoma deposited with the International Depositary Authority of Canada on May 26, 2010 and having accession no. 090310-02. 
     
     
         48 . The dosage form of  claim 42 , wherein said monoclonal antibody or said fragment, portion, variant or derivative thereof, comprises a single-chain antibody, a Fab fragment, F(ab′) 2  fragment, Fd fragment, dAb fragment, scFv, diabody, or bispecific antibody or fragment, portion, or variant thereof. 
     
     
         49 . The dosage form of  claim 42 , wherein said monoclonal antibody or said fragment, portion, variant or derivative thereof, is humanized, veneered or chimeric. 
     
     
         50 . The dosage form of  claim 42 , wherein said monoclonal antibody or said fragment, portion, variant or derivative thereof consists of the monoclonal antibody produced by the hybridoma deposited with the International Depositary Authority of Canada on May 26, 2010 and having accession no. 090310-02. 
     
     
         51 . The dosage form of  claim 42 , wherein the dosage form is formulated for parenteral, intravenous, subcutaneous, intraperitoneal, oral, or intranasal administration. 
     
     
         52 . The dosage form of  claim 42 , wherein the dosage form is administered in combination with a second therapeutic agent. 
     
     
         53 . The dosage form of  claim 52 , wherein the second therapeutic agent is selected from the group consisting of a muscle relaxant, a tranquilizer, an anticonvulsant, a nonsteroidal anti-inflammatory agent, a benzodiazepine, riluzole and amitriptyline. 
     
     
         54 . A method of treating amyotrophic lateral sclerosis (ALS) in a subject, comprising administering to the subject a dosage form of said monoclonal antibody or said fragment, portion, variant or derivative thereof of  claim 42 . 
     
     
         55 . A method of treating or preventing a neurodegenerative condition or for treating a motor neuron disease in a subject, comprising administering to the subject a dosage form of said monoclonal antibody or said fragment, portion, variant or derivative thereof of  claim 42 . 
     
     
         56 . The method of  claim 55 , wherein the motor neuron disease is progressive bulbar palsy, pseudobulbar palsy, primary lateral sclerosis, progressive muscular atrophy, spinal muscular atrophy, SMA Type I, SMA type II, SMA type III, Fazio-Londe disease, Kennedy disease, congenital SMA with arthrogryposis, or post-polio syndrome. 
     
     
         57 . A complex comprising:
 a monoclonal antibody or, a fragment, portion, variant or derivative thereof that recognizes the juxtamembrane region, a peptide within the juxtamembrane region, or a peptide having the amino acid sequence ESTDNFILFDEVSPTPPI (SEQ ID NO: 1), of TrkC; and   TrkC;   
       wherein said monoclonal antibody or said fragment, portion, variant or derivative thereof, specifically binds to the juxtamembrane region, a peptide within the juxtamembrane region, or a peptide having the amino acid sequence ESTDNFILFDEVSPTPPI (SEQ ID NO: 1), of TrkC. 
     
     
         58 . The complex of  claim 57 , wherein said monoclonal antibody or said fragment, portion, variant or derivative thereof, comprises a single-chain antibody, a Fab fragment, F(ab′) 2  fragment, Fd fragment, dAb fragment, scFv, diabody, or bispecific antibody or fragment, portion, or variant thereof. 
     
     
         59 . The complex of  claim 57 , wherein said monoclonal antibody or said fragment, portion, variant or derivative thereof, is humanized, veneered or chimeric. 
     
     
         60 . The complex of  claim 57 , wherein said monoclonal antibody or said fragment, portion, variant or derivative thereof consists of the monoclonal antibody produced by the hybridoma deposited with the International Depositary Authority of Canada on May 26, 2010 and having accession no. 090310-02.