An afucosylated anti-CD20 monoclonal antibody with greater antibody-dependent cellular cytotoxicity and B-cell depletion and lower complement-dependent cytotoxicity than rituximab.
The objective of this study was to characterize the in vitro and in vivo activity of a novel afucosylated rituximab (BLX-300) expressed in a Lemna aquatic plant-based system free of zoonotic pathogens. The glycosylation of BLX-300 was shown to be homogeneous, composed of a single major N-glycan species without detectable fucose or xylose. Target cell binding and induction of apoptosis were similar for BLX-300 and rituximab. Antibody-dependent cellular cytotoxicity (ADCC) was increased by BLX-300 versus rituximab in phenylalanine/phenylalanine (F/F), phenylalanine/valine (F/V) and valine/valine (V/V) genotype donors, as indicated by respective log reductions of 0.82, 1.07 and 0.92 in EC(50). BLX-300 also showed greater B-cell depletion than rituximab in whole blood from donors of F/F, F/V and V/V genotype in vitro and cynomolgus monkeys in vivo. Temporal changes in circulating levels of BLX-300 and rituximab were similar in cynomolgus monkeys. Complement-dependent cytotoxicity (CDC) was attenuated by BLX-300 relative to rituximab, as judged by a log increase of 0.51 in EC(50). The higher ADCC and B-cell depletion suggest a potential improvement in effectiveness and potency, while lower CDC may mitigate infusion toxicity.
Biolex Therapeutics, Pittsboro, NC 27312, USA. jgasdaska@biolex.com
John R
JR
Gasdaska
Steven
S
Sherwood
Jeffrey T
JT
Regan
Lynn F
LF
Dickey
D000818:Animals; D058846:Antibodies, Monoclonal, Murine-Derived / Q000276:immunology* / Q000378:metabolism; D000920:Antibody-Dependent Cell Cytotoxicity; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002460:Cell Line; D005643:Fucose / Q000378:metabolism; D006031:Glycosylation; D008252:Macaca fascicularis; D000069283:Rituximab
D058846:Antibodies, Monoclonal, Murine-Derived; D005643:Fucose; D000069283:Rituximab