Serotherapy of B-cell neoplasms with anti-B4-blocked ricin: a phase I trial of daily bolus infusion

Abstract

Anti-B4-blocked Ricin (Anti-B4-bR) is an immunotoxin comprised of the anti-B4 monoclonal antibody (MoAb) and the protein toxin “blocked ricin.” The anti-B4 MoAb is directed against the B-lineage-restricted CD19 antigen expressed on more than 95% of normal and neoplastic B cells. Blocked ricin is an altered ricin derivative that has its nonspecific binding eliminated by chemically blocking the galactose binding domains of the B chain. In vitro cytotoxicity studies demonstrate that the IC37 of Anti-B4-bR is 2 x 10(-11) mol/L compared with 4 x 10(-12) mol/L for native ricin. A phase I dose escalation clinical trial was conducted in 25 patients with refractory B-cell malignancies. Anti-B4-bR was administered by daily 1-hour bolus infusion for 5 consecutive days at doses ranging from 1 microgram/kg/d to 60 micrograms/kg/d. Serum levels above 1 nmol/L were achieved transiently in the majority of patients treated at the maximum tolerated dose of 50 micrograms/kg/d for 5 days for a total dose of 250 micrograms/kg. The dose-limiting toxicity was defined by transient, reversible grade 3 elevations in hepatic transaminases, without impaired hepatic synthetic function. Minor toxicities included transient hypoalbuminemia, thrombocytopenia, and fevers. Human antimouse antibody and human anti-ricin antibody were detected in nine patients. One complete response, two partial responses, and eight mixed or transient responses were observed. These results show the in vitro and in vivo cytotoxicity of Anti-B4-bR and indicate that this immunotoxin can be administered as a daily bolus infusion for 5 days with tolerable, reversible toxicity.

Anti‐CD30 (BER‐H2) immunotoxins containing the type‐1 ribosome‐inactivating proteins momordin and PAP‐S (pokeweed antiviral protein from seeds) display powerful antitumour activity against CD30+ tumour cells in vitro and in SCID mice

“…As expected from previous work Barbieri et al, 1993), increase of AST and/ or ALT is mostly of liver origin. The hepatotoxicity is probably due to clearance of the IT by the reticuloendothelialsystem in the liver, as suggested in the case of ITs containing ricin-A (Skilleter et al, 1981;Blakey et al, 1988;Grossbard et al, 1992a) and saporin (Battelli et al, 1994).…”

The Role of Intensive Therapy and Autologous Blood and Marrow Transplantation for Chemotherapy‐Sensitive Relapsed and Primary Refractory Non‐Hodgkin’s Lymphoma: Identification of Major Prognostic Groups

“…Consequently, novel additional or alternative approaches are needed for those patients who only achieve a PR with conventional-dose salvage therapy. These include the use of multiple cycle intensive therapy (Van Besien et al, 1994), modifiers of multidrug resistance (Frei & Freireich, 1993), allogeneic marrow or blood cell transplantation (Ratanatharathorn et al, 1994;Demirer et al, 1995;Mendoza et al, 1995), immunomodulation therapy (Givon et al, 1994;Soiffer et al, 1993;Gisselbrecht et al, 1994;Weisdorf et al, 1994), immunotoxin therapy (Grossbard et al, 1992;Vallera, 1994) and therapeutic radioimmunoconjugates (Parker et al, 1990).…”

Anti‐B4‐blocked ricin: a phase II trial of 7 day continuous infusion in patients with multiple myeloma

“…Immunotoxins have not been used previously to treat patients with multiple myeloma, but they have shown promising in vitro activity against tumour cells obtained from the bone marrow of patients with multiple myeloma ( Dinota et al , 1989 ; Goldmacher et al , 1994 ; Kreitman et al , 1992 ). We previously developed extensive experience with anti‐B4‐bR in the treatment of patients with B‐cell non‐Hodgkin's lymphoma (NHL), chronic lymphocytic leukaemia, and acute lymphoblastic leukaemia ( Grossbard et al , 1992 , 1993b). Although anti‐B4‐bR could be administered safely to patients by 7 d continuous infusion, antigen excess remained a difficult problem to overcome when treating patients with bulky relapsed tumours.…”