MGD011, A CD19 x CD3 Dual-Affinity Retargeting Bi-specific Molecule Incorporating Extended Circulating Half-life for the Treatment of B-Cell Malignancies.
Purpose:CD19, a B-cell lineage-specific marker, is highly represented in B-cell malignancies and an attractive target for therapeutic interventions. MGD011 is a CD19 x CD3 DART bispecific protein designed to redirect T lymphocytes to eliminate CD19-expressing cells. MGD011 has been engineered with a modified human Fc domain for improved pharmacokinetic (PK) properties and designed to cross-react with the corresponding antigens in cynomolgus monkeys. Here, we report on the preclinical activity, safety and PK properties of MGD011.Experimental Design:The activity of MGD011 was evaluated in severalin vitroandin vivomodels. PK, safety and pharmacodynamic activity was also assessed in dose-escalation and repeat-dose studies of MGD011 administered once weekly in cynomolgus monkeys.Results:MGD011 mediated killing of human B-cell lymphoma lines by human or cynomolgus monkey PBMCs as well as autologous B-cell depletion in PBMCs from both species. MGD011-mediated killing was accompanied by target-dependent T-cell activation and expansion, cytokine release and upregulation of perforin and granzyme B. MGD011 demonstrated antitumor activity against localized and disseminated lymphoma xenografts reconstituted with human PBMCs. In cynomolgus monkeys, MGD011 displayed a terminal half-life of 6.7 days; once weekly intravenous infusion of MGD011 at doses up to 100 μg/kg, the highest dose tested, was well tolerated and resulted in dose-dependent, durable decreases in circulating B cells accompanied by profound reductions of B lymphocytes in lymphoid organs.Conclusions:The preclinical activity, safety and PK profile support clinical investigation of MGD011 as a therapeutic candidate for the treatment of B-cell malignancies.Clin Cancer Res; 23(6); 1506-18. ©2016 AACR.
Research, MacroGenics, Inc., Rockville, Maryland.
Liqin
L
Liu
Research, MacroGenics, Inc., Rockville, Maryland.
Chia-Ying K
CK
Lam
Research, MacroGenics, Inc., Rockville, Maryland.
Vatana
V
Long
Research, MacroGenics, Inc., Rockville, Maryland.
Lusiana
L
Widjaja
Research, MacroGenics, Inc., Rockville, Maryland.
Yinhua
Y
Yang
Research, MacroGenics, Inc., Rockville, Maryland.
Hua
H
Li
Research, MacroGenics, Inc., Rockville, Maryland.
Linda
L
Jin
Research, MacroGenics, Inc., Rockville, Maryland.
Steve
S
Burke
Research, MacroGenics, Inc., Rockville, Maryland.
Sergey
S
Gorlatov
Research, MacroGenics, Inc., Rockville, Maryland.
Jennifer
J
Brown
Research, MacroGenics, Inc., Rockville, Maryland.
Ralph
R
Alderson
Research, MacroGenics, Inc., Rockville, Maryland.
Margaret D
MD
Lewis
Research, MacroGenics, Inc., Rockville, Maryland.
Jeffrey L
JL
Nordstrom
Research, MacroGenics, Inc., Rockville, Maryland.
Scott
S
Koenig
Research, MacroGenics, Inc., Rockville, Maryland.
Paul A
PA
Moore
Research, MacroGenics, Inc., Rockville, Maryland.
Syd
S
Johnson
Research, MacroGenics, Inc., Rockville, Maryland. bonvinie@macrogenics.com.
Ezio
E
Bonvini
D000818:Animals; D018033:Antibodies, Bispecific / Q000008:administration & dosage* / Q000276:immunology; D018941:Antigens, CD19 / Q000276:immunology* / Q000627:therapeutic use; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008252:Macaca fascicularis; D051379:Mice; D013601:T-Lymphocytes / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
D018033:Antibodies, Bispecific; D018941:Antigens, CD19; C000604811:CD19 molecule, human