RT Journal Article
SR Electronic
T1 Characterization of 7A5: A Human CD137 (4-1BB) Receptor Binding Monoclonal Antibody with Differential Agonist Properties That Promotes Antitumor Immunity
JF Molecular Cancer Therapeutics
JO Mol Cancer Ther
FD American Association for Cancer Research
SP 988
OP 998
DO 10.1158/1535-7163.MCT-19-0893
VO 19
IS 4
A1 Kotanides, Helen
A1 Sattler, Rose Marie
A1 Lebron, Maria B.
A1 Carpenito, Carmine
A1 Shen, Juqun
A1 Li, Jingxing
A1 Surguladze, David
A1 Haidar, Jaafar N.
A1 Burns, Colleen
A1 Shen, Leyi
A1 Inigo, Ivan
A1 Pennello, Anthony L.
A1 Forest, Amelie
A1 Chen, Xinlei
A1 Chin, Darin
A1 Sonyi, Andreas
A1 Topper, Michael
A1 Boucher, Lauren
A1 Sharma, Prachi
A1 Zhang, Yiwei
A1 Burtrum, Douglas
A1 Novosiadly, Ruslan D.
A1 Ludwig, Dale L.
A1 Plowman, Gregory D.
A1 Kalos, Michael
YR 2020
UL http://mct.aacrjournals.org/content/19/4/988.abstract
AB The CD137 receptor plays a key role in mediating immune response by promoting T cell proliferation, survival, and memory. Effective agonism of CD137 has the potential to reinvigorate potent antitumor immunity either alone or in combination with other immune-checkpoint therapies. In this study, we describe the discovery and characterization of a unique CD137 agonist, 7A5, a fully human IgG1 Fc effector-null monoclonal antibody. The biological properties of 7A5 were investigated through in vitro and in vivo studies. 7A5 binds CD137, and the binding epitope overlaps with the CD137L binding site based on structure. 7A5 engages CD137 receptor and activates NF-κB cell signaling independent of cross-linking or Fc effector function. In addition, T cell activation measured by cytokine IFNγ production is induced by 7A5 in peripheral blood mononuclear cell costimulation assay. Human tumor xenograft mouse models reconstituted with human immune cells were used to determine antitumor activity in vivo. Monotherapy with 7A5 inhibits tumor growth, and this activity is enhanced in combination with a PD-L1 antagonist antibody. Furthermore, the intratumoral immune gene expression signature in response to 7A5 is highly suggestive of enhanced T cell infiltration and activation. Taken together, these results demonstrate 7A5 is a differentiated CD137 agonist antibody with biological properties that warrant its further development as a cancer immunotherapy.Graphical Abstract: http://mct.aacrjournals.org/content/molcanther/19/4/988/F1.large.jpg.This article is featured in Highlights of This Issue, p. 973