T-cell activation and B-cell depletion in chimpanzees treated with a bispecific anti-CD19/anti-CD3 single-chain antibody construct.
BscCD19xCD3 is a bispecific single-chain antibody construct with exceptional cytotoxic potency in vitro and in vivo. Here, we have investigated the biological activity of bscCD19xCD3 in chimpanzee, the only animal species identified in which bscCD19xCD3 showed bispecific binding, redirected B-cell lysis and cytokine production comparable to human cells. Pharmacokinetic analysis following 2-h intravenous infusion of 0.06, 0.1 or 0.12 mug/kg of bscCD19xCD3 as part of a dose escalation study in a single female chimpanzee revealed a half-life of approximately 2 h and elimination of the bispecific antibody from circulation within approximately 8 h after the end of infusion. This short exposure to bscCD19xCD3 elicited a transient increase in serum levels of IFNgamma, IL-6, IL-2, soluble CD25, and transiently upregulated expression of CD69 and MHC class II on CD8-positive cells. Cytokine release and upregulation of T-cell activation markers were not observed with vehicle controls. A multiple-dose study using 5 weekly doses of 0.1 mug/kg in two animals also showed transient cytokine release and an activation of peripheral T cells with a first-dose effect, accompanied by a transient lymphopenia. While oscillations of T-cell counts were relatively even during repeated treatments, the amplitudes of peripheral B cells declined with every infusion, which was not observed in a vehicle control animal. Our data show that bscCD19xCD3 can be safely administered to chimpanzees at dose levels that cause fully reversible T-cell activation and, despite a very short exposure time, cumulative loss of peripheral B lymphocytes. A clinical trial testing prolonged administration of bscCD19xCD3 (MT103) for improving efficacy is currently ongoing.
Schlereth
Bernd
B
Micromet AG, Staffelseestr. 2, 81477, Munich, Germany.
Quadt
Cornelia
C
Dreier
Torsten
T
Kufer
Peter
P
Lorenczewski
Grit
G
Prang
Nadja
N
Brandl
Christian
C
Lippold
Sandra
S
Cobb
Kathy
K
Brasky
Kathleen
K
Leo
Eugen
E
Bargou
Ralf
R
Murthy
Krishna
K
Baeuerle
Patrick A
PA
D000818:Animals; D018033:Antibodies, Bispecific / Q000493:pharmacokinetics*; D018941:Antigens, CD19 / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007167:Immunotherapy; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D008212:Lymphocyte Depletion; D008297:Male; D002679:Pan troglodytes; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D018033:Antibodies, Bispecific; D018941:Antigens, CD19; D017252:CD3 Complex