Locoregional treatment of low‐grade B‐cell lymphoma with CD3×CD19 bispecific antibodies and CD28 costimulation: I. Clinical phase I evaluation

• Published in: International journal of cancer Vol. 91; no. 4; pp. 508 - 515
• Main Authors: Manzke, Oliver, Tesch, Hans, Borchmann, Peter, Wolf, Jürgen, Lackner, Klaus, Gossmann, Axel, Diehl, Volker, Bohlen, Heribert
• Format: Journal Article
• Language: English
• Published: New York John Wiley & Sons, Inc 15.02.2001; Wiley-Liss
• Subjects: Antineoplastic agents; Biological and medical sciences; bispecific antibody; B‐cell lymphoma; Immunotherapy; Medical sciences; Pharmacology. Drug treatments; Phase I study; Antineoplastic agent; Regional treatment; Immune response; Antibody; Intratumoral administration; Malignant hemopathy; B-Lymphocyte; Bispecific antibody; Non Hodgkin lymphoma; Signal transduction; Lymphoproliferative syndrome; Low malignancy; Immunotherapy; Phase I trial
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/1097-0215(200002)9999:9999<::AID-IJC1068>3.0.CO;2-D

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 CD3×CD19 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 μg: 3 patients; 270 μg: 3 patients; 810 μg: 3 patients; 1,600 μg: 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 μg of injected antibodies. Three patients showed a serum peak of TNFα 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 CD3×CD19+CD28 antibodies is feasible up to a dose of at least 1,600 μg of each antibody. However, the development of human anti‐mouse antibodies points toward the requirement for new formats of bispecific proteins with reduced immunogenicity. © 2001 Wiley‐Liss, Inc.