Cloning, expression and characterization of monkey (Macaca fascicularis) CD137.
CD137 plays an important role as a co-stimulatory molecule in activated T cells. Agonistic CD137 specific antibodies have been investigated as therapeutic agents to promote tumor-specific immune responses by direct activation of T cells. As part of the pre-clinical pharmacological evaluation of cynomolgus monkeys, monkey CD137 was cloned and characterized. The deduced amino acid sequence encoded a full-length gene of 254 amino acids 95% identical to human CD137. Sequence variants identified in monkey CD137 include four splice variants lacking the transmembrane domain. These variants were detectable in human including two previously unreported variants. Two missense single nucleotide polymorphisms were detected present in 42 and 50% of 36 monkeys tested. In both monkey and human, mRNA expression of full-length CD137 and splice variants were significantly increased in peripheral blood mononuclear cells (PBMCs) upon stimulation by anti-CD3 antibodies. Recombinant monkey CD137 protein was bound with high affinity by an agonistic anti-human CD137 antibody but not by an anti-mouse CD137 antibody. In summary, compared to human, monkey CD137 showed distinct extracellular domain amino acid sequence and sequence polymorphisms. Thus, antibodies directed against epitopes in this extracellular domain could have differences in pharmacologic activity between cynomolgus monkeys and human or across individual cynomolgus monkeys.
Chen
Shen-Jue
SJ
Discovery Toxicology, Bristol-Myers Squibb Research and Development, Route 206 & Province Line Road, Princeton, NJ 08543, United States. shenjue.chen@bms.com
Foster
William R
WR
Jure-Kunkel
Maria N
MN
Girit
Emel
E
Abraham
Ralph
R
Hefta
Laura J
LJ
Gao
Shan
S
Yonan
Christopher R
CR
Lin
Jun-Hsiang
JH
Dambach
Donna M
DM
D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000378:metabolism; D001483:Base Sequence; D003001:Cloning, Molecular; D017931:DNA Primers / Q000235:genetics; D006801:Humans; D008252:Macaca fascicularis / Q000235:genetics*; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000662:veterinary; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA / Q000662:veterinary; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics* / Q000378:metabolism*
D000906:Antibodies; D017931:DNA Primers; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9