Altered polypeptides with increased half-life

Abstract

Polypeptides that are cleared from the kidney and do not contain in their original form a Fc region of an IgG are altered so as to comprise a salvage receptor binding epitope of an Fc region of an IgG and thereby have increased circulatory half-life.

1 . Nucleic acid encoding a polypeptide variant of a polypeptide of interest which polypeptide of interest is cleared from the kidney and does not contain a Fc region of an IgG, which variant comprises a salvage receptor binding epitope of an Fc region of an IgG, and which variant has a longer in vivo half-life than the polypeptide of interest. 
     
     
         2 . The nucleic acid of  claim 1  wherein the polypeptide of interest contains an Ig domain or Ig-like domain that is not a CH2 domain. 
     
     
         3 . The nucleic acid of  claim 2  wherein the epitope is contained within the Ig domain or Ig-like domain. 
     
     
         4 . The nucleic acid of  claim 3  wherein the Ig domain or Ig-like domain comprises a CH1 domain. 
     
     
         5 . The nucleic acid of  claim 3  wherein the epitope is taken from one or two loops of the Fc region and transferred to the Ig domain or Ig-like domain. 
     
     
         6 . The nucleic acid of  claim 5  wherein the epitope is taken from the CH2 domain of the Fc region and transferred to the CH1, CH3, or V H  region, or more than one such region, of an Ig or to a Ig-like domain. 
     
     
         7 . The nucleic acid of  claim 5  wherein the epitope is taken from the CH2 domain of the Fc region and transferred to the CL region or V L  region, or both, of an Ig or to an Ig-like domain. 
     
     
         8 . The nucleic acid of  claim 3  wherein the polypeptide of interest is a Fab, a (Fab′) 2 , a diabody, a Fv fragment, a single-chain Fv fragment, or a receptor. 
     
     
         9 . The nucleic acid of  claim 8  wherein the polypeptide of interest is an LFA-1 antagonist. 
     
     
         10 . The nucleic acid of  claim 9  wherein the polypeptide of interest is a Fab or (Fab′) 2  of an anti-LFA-1 antibody. 
     
     
         11 . The nucleic acid of  claim 10  wherein the polypeptide of interest is an anti-CD18 Fab or anti-CD18 (Fab′) 2 . 
     
     
         12 . The nucleic acid of  claim 11  wherein the polypeptide of interest is human or humanized. 
     
     
         13 . The nucleic acid of  claim 1  wherein the epitope comprises the sequences: HQNLSDGK (SEQ ID NO: 1), HQNISDGK (SEQ ID NO: 2), HQSLGTQ (SEQ ID NO: 11), or VISSHLGQ (SEQ ID NO: 31) and PKNSSMISNTP (SEQ ID NO: 3). 
     
     
         14 . The nucleic acid of  claim 13  wherein the epitope is fused to the polypeptide of interest. 
     
     
         15 . The nucleic acid of  claim 14  wherein the polypeptide of interest is growth hormone or nerve growth factor. 
     
     
         16 . A replicable vector comprising the nucleic acid of  claim 1 . 
     
     
         17 . A host cell comprising the nucleic acid of  claim 1 . 
     
     
         18 . A host cell that is transformed with the nucleic acid of  claim 1 . 
     
     
         19 . A method for producing a polypeptide variant comprising culturing the host cells of  claim 1  in a culture medium and recovering the variant from the host cell culture. 
     
     
         20 . The method of  claim 19  wherein the variant is recovered from the host cell culture medium.