Ig/ob fusions and uses thereof.

Abstract

The present invention stems from the observation that administration of OB protein to non-obese as well as obese animals results in an increase of lean tissue mass. Thus, OB protein has the capacity to act, in addition to acting as a weight reducing agent, as an agent affecting lean tissue mass. As such, numerous lean tissue-mass increasing therapies are contemplated, even for patients who would not necessarily benefit from weight reduction. Thus, one aspect of the present invention is the use of OB protein (or analogs or derivatives thereof) for increasing lean tissue mass.

1 . A method for increasing lean tissue mass, comprised of administering an effective amount of an OB protein, analog or derivative thereof selected from among: 
 (a) the amino acid sequence 1-146 as set forth in SEQ. ID. NO. 2 or SEQ ID. NO. 4 ;    (b) the amino acid sequence 1-146 as set forth in SEQ. ID. NO. 4 having a lysine residue at position 35 and an isoleucine residue at position 74;    (c) the amino acid sequence of subpart (b) having a different amino acid substituted in one or more of the following positions (using the numbering according to SEQ. ID. NO. 4): 4, 8, 32, 33, 35, 48, 50, 53, 60, 64, 66, 67, 68, 71, 74, 77, 78, 89, 97, 100, 102, 105, 106, 107, 108, 111, 112, 118, 136, 138, 142, and 145;    (d) the amino acid sequence of subparts (a), (b) or (c) optionally lacking a glutaminyl residue at position 28;    (e) the amino acid sequence of subparts (a), (b), (c), or (d) having a methionyl residue at the n terminus:    (f) a truncated OB protein analog selected from among: (using the numbering of SEQ. ID. NO. 4 having a lysine residue at position 35, and an isoleucine residue at position 74): 
 (i) amino acids 98-146  
 (ii) amino acids 1-32  
 (iii) amino acids 40-116  
 (iv) amino acids 1-99 and 112-146  
 (v) amino acids 1-99 and 112-146 having one or more of amino acids 100-111 sequentially placed between amino acids 99 and 112; and,  
 (vi) the truncated OB analog of subpart (f)(i) having one or more of amino acids 100, 102, 105, 106, 107, 108, 111, 112, 118, 136, 138, 142, and 145 substituted with another amino acid;  
 (vii) the truncated analog of subpart (f)(ii) having one or more of amino acids 4, 8 and 32 substituted with another amino acid;  
 (viii) the truncated analog of subpart (f)(iii) having one or more of amino acids 50, 53, 60, 64, 66, 67, 68, 71, 74, 77, 78, 89, 97, 100, 102, 105, 106, 107, 108, 111 and 112 replaced with another amino acid;  
 (vix) the truncated analog of subpart (f)(iv) having one or more of amino acids 4, 8, 32, 33, 35, 48, 50, 53, 60, 64, 66, 67, 68, 71, 74, 77, 78, 89, 97, 112, 118, 136, 138, 142, and 145 replaced with another amino acid;  
 (x) the truncated analog of subpart (f)(v) having one or more of amino acids 4, 8, 32, 33, 35, 48, 50, 53, 60, 64, 66, 67, 68, 71, 74, 77, 78, 89, 97, 100, 102, 105, 106, 107, 108, 111, 112, 118, 136, 138, 142, and 145 replaced with another amino acid;  
 (xi) the truncated analog of any of subparts (f)(i)-(x) having an N-terminal methionyl residue; and  
   (g) the OB protein or analog derivative of any of subparts (a) through (f) comprised of a chemical moiety connected to the protein moiety;    (h) a derivative of subpart (g) wherein said chemical moiety is a water soluble polymer moiety;    (i) a derivative of subpart (h) wherein said water soluble polymer moiety is polyethylene glycol;    (j) A derivative of subpart (h) wherein said water soluble polymer moiety is a polyamino acid moiety;    (k) a derivative of subpart (h) wherein said water soluble polymer moiety is attached at solely the N-terminus of said protein moiety;    (l) an OB protein, analog or derivative of any of subparts (a) through (k) in a pharmaceutically acceptable carrier.    
     
     
         2 . A method of  claim 1  wherein said method also provides for an increased sensitivity to insulin.  
     
     
         3 . A method of  claim 1  wherein said method also provides for an increase in overall body strength.  
     
     
         4 . A method of  claim 1  wherein said method also provides for decreased bone resorption.