title: Phase 1 trial of the novel bispecific molecule H22xKi-4 in patients with refractory Hodgkin lymphoma.
abstract: CD30 is an excellent target for immunotherapy of Hodgkin lymphoma (HL) because it is overexpressed on Hodgkin and Reed-Sternberg cells. We developed a novel bispecific molecule (BSM) consisting of F(ab') fragments derived from the murine anti-CD30 monoclonal antibody (MoAb) Ki-4 and the humanized CD64-specific MoAb H22. In vitro experiments of H22xKi-4 demonstrated specific phagocytosis of HL-derived cell lines. Patients (pts) with refractory CD30(+) HL were treated with escalating doses of H22xKi-4 at doses of 1, 2.5, 5, 10, and 20 mg/m(2)/d, respectively (administered intravenously on days 1, 3, 5, and 7). The main study objectives were to determine the maximum tolerated dose and the dose-limiting toxicities of H22xKi-4, to define its pharmacokinetic profile, and to document clinical response. Ten pts were enrolled and are evaluable for toxicity and response. Side effects were transient and mild with hypotension (4 of 10), tachycardia (6 of 10), fatigue (10 of 10), and fever (2 of 10 grade I, 3 of 10 grade II). Pharmacokinetic (PK) data revealed an elimination half-life of 11.1 hours, resulting in a significant accumulation of H22xKi-4. The BSM was shown to bind to both monocytes and malignant cells. Response to H22xKi-4 included 1 complete remission (CR), 3 partial remissions (PR), and 4 pts with stable disease. The new BSM H22xKi-4 can be given safely to pts with refractory CD30(+) HL in doses up to 80 mg/m(2) per cycle. Although this dose is not the maximum tolerated dose (MTD) as defined by toxicity criteria, surrogate parameters suggest a biologic effective regimen. H22xKi-4 shows activity in heavily pretreated HL patients warranting further clinical evaluation.
authors.affiliation: Klinik I für Innere Medizin der Universität Köln, Joseph-Stelzmannstrasse 9, 50924 Köln, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Borchmann
authors.forename: Roland
authors.initials: R
authors.lastname: Schnell
authors.forename: Irene
authors.initials: I
authors.lastname: Fuss
authors.forename: Oliver
authors.initials: O
authors.lastname: Manzke
authors.forename: Thomas
authors.initials: T
authors.lastname: Davis
authors.forename: Lionel D
authors.initials: LD
authors.lastname: Lewis
authors.forename: Detlev
authors.initials: D
authors.lastname: Behnke
authors.forename: Claudia
authors.initials: C
authors.lastname: Wickenhauser
authors.forename: Petra
authors.initials: P
authors.lastname: Schiller
authors.forename: Volker
authors.initials: V
authors.lastname: Diehl
authors.forename: Andreas
authors.initials: A
authors.lastname: Engert
mesh_terms: D000328:Adult; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000096:biosynthesis; D018033:Antibodies, Bispecific / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000912:Antibodies, Neoplasm / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000951:Antigens, Neoplasm / Q000276:immunology; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005334:Fever / Q000139:chemically induced; D006207:Half-Life; D006689:Hodgkin Disease / Q000628:therapy*; D006801:Humans; D007022:Hypotension / Q000139:chemically induced; D007167:Immunotherapy; D017730:Ki-1 Antigen / Q000276:immunology; D008297:Male; D020714:Maximum Tolerated Dose; D051379:Mice; D008875:Middle Aged; D010587:Phagocytosis; D017452:Receptors, IgG / Q000276:immunology; D012074:Remission Induction; D012449:Safety; D016879:Salvage Therapy; D013610:Tachycardia / Q000139:chemically induced; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: D000888:Antibodies, Anti-Idiotypic; D018033:Antibodies, Bispecific; D000912:Antibodies, Neoplasm; D000951:Antigens, Neoplasm; D017730:Ki-1 Antigen; D017452:Receptors, IgG