Locoregional treatment of low-grade B-cell lymphoma with CD3xCD19 bispecific antibodies and CD28 costimulation. I. Clinical phase I evaluation.
We describe the first clinical application of T-cell-recruiting bispecific antibodies directly into the tumor without the need to preactivate the effector cells. In a Phase I clinical trial, 10 patients with low-grade B-cell lymphoma were treated by a single locoregional injection of CD3xCD19 bispecific antibodies. Costimulatory signaling, which is required for the optimal activation of resting T cells, was provided by the simultaneous administration of CD28 antibodies. Equal amounts of both antibodies were injected together at 4 different dose levels (30 microg: 3 patients; 270 microg: 3 patients; 810 microg: 3 patients; 1,600 microg: 1 patient). The injection was well tolerated with mild to moderate adverse effects (2/10 patients) consisting of erythema and fever at the third dose level. The maximum tolerated dose was not reached at 810 microg of injected antibodies. Three patients showed a serum peak of TNFalpha on day 2 or 3 after the antibody application, reflecting rather an activation of CD4-positive T cells than an FcR-mediated effect. Five patients developed anti-mouse antibodies after injection of the murine immunoglobulins. Nine patients were evaluable for restaging examinations 6 weeks after the antibody application, with 2 of them (22%) showing a local clinical response. We found that a single locoregional injection of CD3xCD19+CD28 antibodies is feasible up to a dose of at least 1,600 microg of each antibody. However, the development of human anti-mouse antibodies points toward the requirement for new formats of bispecific proteins with reduced immunogenicity.
Manzke
O
O
University of Cologne, Department of Internal Medicine I, Joseph-Stelzmann-Str.9, D-50925 Cologne, Germany.
Tesch
H
H
Borchmann
P
P
Wolf
J
J
Lackner
K
K
Gossmann
A
A
Diehl
V
V
Bohlen
H
H
D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D018033:Antibodies, Bispecific / Q000008:administration & dosage / Q000627:therapeutic use*; D018941:Antigens, CD19 / Q000627:therapeutic use*; D018106:CD28 Antigens / Q000627:therapeutic use*; D017252:CD3 Complex / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism; D007167:Immunotherapy; D015448:Leukemia, B-Cell / Q000628:therapy; D008198:Lymph Nodes / Q000378:metabolism; D008213:Lymphocyte Activation; D016393:Lymphoma, B-Cell / Q000628:therapy*; D008224:Lymphoma, Follicular / Q000628:therapy; D020522:Lymphoma, Mantle-Cell / Q000628:therapy; D008297:Male; D051379:Mice; D008875:Middle Aged; D008954:Models, Biological; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018033:Antibodies, Bispecific; D018941:Antigens, CD19; D018106:CD28 Antigens; D017252:CD3 Complex; D016207:Cytokines; D007136:Immunoglobulins; D014409:Tumor Necrosis Factor-alpha