Long acting luteinizing hormone (lh) compound

Abstract

The present invention relates to a long acting biologically active luteinizing hormone (LH) compound comprising an LH agonist linked to a pharmaceutically acceptable molecule providing an in vivo plasma half-life of the LH agonist or LH compound which is increased substantially compared to the in vivo plasma half-life of an LH agonist administered in the same manner as the LH compound. The present invention relates to methods for controlled ovarian stimulation which can be used in conjunction with assisted reproduction technologies such as in vitro fertilisation, intra cytoplasmatic sperm injection, intra uterine insemination and in vitro maturation. In other aspects the invention relates to methods for inducing folliculogenesis and methods for providing luteal support for the corpora lutea.

We claim: 
     
         1 . A long acting biologically active luteinizing hormone (LH) compound comprising a mammal CG or analog thereof or a mammal LH or analog thereof linked to a pharmaceutically acceptable molecule selected from a molecule having binding to a mammal neonatal Fc receptor, transferrin and a CH 3 (CH 2 ) n CO—, wherein n is 8 to 22 and a polymer. 
     
     
         2 . The LH compound of  claim 1  wherein the pharmaceutically acceptable molecule is selected from a molecule having binding to a mammal neonatal Fc receptor. 
     
     
         3 . The LH compound of  claim 1  wherein the pharmaceutically acceptable molecule is selected from an albumin, an Fc fragment of a mammalian antibody, and a variant of an Fc fragment of a mammalian antibody. 
     
     
         4 . The LH compound of  claim 1  wherein the pharmaceutically acceptable molecule is selected from an albumin such as human albumin, recombinant human albumin, a modified human albumin with increased binding to a mammal FcRn, a modified recombinant albumin with increased binding to a mammal FcRn. 
     
     
         5 . The LH compound of  claim 1  wherein the mammal CG or analog thereof or a mammal LH or analog thereof is selected from recombinant mammal CG or analog thereof or mammal LH or analog thereof. 
     
     
         6 . The LH compound of  claim 5  wherein the recombinant mammal CG or analog thereof is selected from the sequence of primate CG, such as human CG, abe CG or monkey CG; and the sequence of equine CG, such as horse CG or wherein the recombinant mammal LH or analog thereof is selected from the sequence of primate LH, such as human LH, abe LH or monkey LH; the sequence of cow LH; the sequence pig LH; the sequence of equine LH, such as horse LH; the sequence of sheep LH; the sequence of dog LH; the sequence of cat LH; and the sequence of goat LH. 
     
     
         7 . The LH compound of  claim 1  wherein the mammal CG or analog thereof or a mammal LH or analog thereof is selected from an analog that has at least 80% identity to the corresponding mammalian sequence of chorionic gonadotropin or luteinizing hormone, respectively, such as 85% identity, 90% identity, 95% identity, 98% identity. 
     
     
         8 . The LH compound of  claim 1  wherein the pharmaceutically acceptable molecule is selected from PEG, e.g. PEG of a molecular weight of at least 5 kDa, such as from 10 kDa to 150 kDa, typically 10 to 40 kDa. 
     
     
         9 . The LH compound of  claim 1  wherein the chemical linker is selected from a sugar moiety, a disulphide bridge, a hydrophilic linker, a hydrolysable linker, dicarboxylic acids, carboxylic acid hydrazides, maleimido hydrazides, PDPH, SPDP, LC-SPDP, GMBS, alkyl linkers, and PEG linkers. 
     
     
         10 . The LH compound of  claim 1  wherein the mammal CG or analog thereof or a mammal LH or analog thereof is directly chemically linked to the pharmaceutically acceptable molecule, wherein the pharmaceutically acceptable molecule is linked to the alfa chain of the mammal CG or analog thereof or the mammal LH or analog thereof or wherein the pharmaceutically acceptable molecule is linked to the beta chain of the mammal CG or analog thereof or the mammal LH or analog thereof. 
     
     
         11 . The LH compound of  claim 1  wherein the mammal CG or analog thereof or a mammal LH or analog thereof is fused to the pharmaceutically acceptable molecule selected from a molecule having binding to a mammal neonatal Fc receptor, such as an albumin, an Fc fragment of a mammalian antibody, or a variant of an Fc fragment of a mammalian antibody, optionally through a peptide linker. 
     
     
         12 . The LH compound of  claim 11  wherein the peptide linker has at least 1 amino acid, such as from 1-200 amino acids, typically 1-50 amino acids wherein the amino acids are selected from the twenty naturally occurring amino acids. 
     
     
         13 . The LH compound of  claim 11  wherein the mammal CG or analog thereof or a mammal LH or analog thereof is directly fused to the pharmaceutically acceptable molecule. 
     
     
         14 . The LH compound of  claim 11  wherein the pharmaceutically acceptable molecule is fused to an N-terminal of the mammal CG or analog thereof or an N-terminal of the mammal LH or analog thereof, wherein the pharmaceutically acceptable molecule is fused to the N-terminal of the alfa chain of the mammal CG or analog thereof or the N-terminal of the alfa chain of the mammal LH or analog thereof or wherein the pharmaceutically acceptable molecule is fused to the N-terminal of the beta chain of the mammal CG or analog thereof or the N-terminal of the beta chain of the mammal LH or analog thereof. 
     
     
         15 . The LH compound of  claim 11  wherein the pharmaceutically acceptable molecule is fused to a C-terminal of the mammal CG or analog thereof or a C-terminal of mammal LH or analog thereof, wherein the pharmaceutically acceptable molecule is fused to the C-terminal of the alfa chain of the mammal CG or analog thereof or the C-terminal of the alfa chain of the mammal LH or analog thereof or wherein the pharmaceutically acceptable molecule is fused to the C-terminal of the beta chain of the mammal CG or analog thereof or the C-terminal of the beta chain of the mammal LH or analog thereof. 
     
     
         16 . The LH compound of  claim 1  wherein the mammalian CG or analog thereof or the mammalian LH or analog thereof is glycosylated. 
     
     
         17 . The LH compound of  claim 1  wherein mammal CG or analog thereof or a mammal LH or analog thereof is selected from one mammal CG or analog thereof or one mammal LH or analog thereof. 
     
     
         18 . The LH compound of  claim 1  selected from Conjugate) (hCG-PDPH-rHA conjugate), Conjugate3 (hCG-SPDP-rHA conjugate), Conjugate4 (EDC activated hCG-PDPH-rHA conjugate) Conjugate3V1 (hCG-SPDP-rHA-K573P conjugate), Conjugate4V1 (EDC activated hCG-PDPH-rHA-K573P conjugate) Product2 consisting of SEQ ID NO:9 and SEQ ID NO:26, Product3 consisting of SEQ ID NO:1 and SEQ ID NO:28, Product4 consisting of SEQ ID NO:9 and SEQ ID NO:27, Product5 consisting of SEQ ID NO:1 and SEQ ID NO:29, Product7 consisting of SEQ ID NO:4 and SEQ ID NO:26, Product8 consisting of SEQ ID NO:1 and SEQ ID NO:30, Product9 consisting of SEQ ID NO:4 and SEQ ID NO:27, Product10 consisting of SEQ ID NO:1 and SEQ ID NO: 31, Product11 consisting of SEQ ID NO:32 and SEQ ID NO: 33, Product12 consisting of SEQ ID NO:32 and SEQ ID NO:34, Product13 consisting of SEQ ID NO:32 and SEQ ID NO:61, Product14 consisting of SEQ ID NO:32 and SEQ ID NO:62. 
     
     
         19 . A composition comprising the compound of  claim 1 . 
     
     
         20 . A method for assisted reproductive therapy in a female human, said method comprising
 a. starting stimulation by administering FSH on cycle day 1-3 of a menstrual cycle,   b. administering a GnRH antagonist from day 4-7 of the stimulation until ovulation triggering,   c. providing an LH compound of  claim 1  to said female by administering at least one dosage of an LH agonist in the period from day 1-9 of the stimulation, said dosage being sufficient to stimulate follicle development until ovulation triggering,   d. discontinuing administration of FSH when at least one follicle has a diameter of 12-14 mm,   e. inducing ovulation with at least one dosage of a GnRH agonist when at least one follicle has a diameter of at least 15 mm.