Effects of the Intermolecular Toxin-Monoclonal Antibody Linkage on the In Vivo Stability, Immunogenicity and Anti-Leukemic Activity of B43 (Anti-CD19) Pokeweed Antiviral Protein Immunotoxin

Fatih M. Uckun Tumor Immunology Laboratory, Section of Cancer and Leukemia Biology, Department of Therapeutic Radiology-Radiation Oncology; Division of Hematology/Oncology/Bone Marrow Transplant Program, Department of Pediatrics; Department of Pharmacology, University of Minnesota, Minneapolis, MN; Department of Chemistry, Southwest Texas State University, San Marcos, TX; Chiron Corporation, Emeryville, CA, USA

Dorothea E. Myers Tumor Immunology Laboratory, Section of Cancer and Leukemia Biology, Department of Therapeutic Radiology-Radiation Oncology; Division of Hematology/Oncology/Bone Marrow Transplant Program, Department of Pediatrics; Department of Pharmacology, University of Minnesota, Minneapolis, MN; Department of Chemistry, Southwest Texas State University, San Marcos, TX; Chiron Corporation, Emeryville, CA, USA

James D. Irvin Tumor Immunology Laboratory, Section of Cancer and Leukemia Biology, Department of Therapeutic Radiology-Radiation Oncology; Division of Hematology/Oncology/Bone Marrow Transplant Program, Department of Pediatrics; Department of Pharmacology, University of Minnesota, Minneapolis, MN; Department of Chemistry, Southwest Texas State University, San Marcos, TX; Chiron Corporation, Emeryville, CA, USA

Virginia M. Kuebelbeck Tumor Immunology Laboratory, Section of Cancer and Leukemia Biology, Department of Therapeutic Radiology-Radiation Oncology; Division of Hematology/Oncology/Bone Marrow Transplant Program, Department of Pediatrics; Department of Pharmacology, University of Minnesota, Minneapolis, MN; Department of Chemistry, Southwest Texas State University, San Marcos, TX; Chiron Corporation, Emeryville, CA, USA

Dale Finnegan Tumor Immunology Laboratory, Section of Cancer and Leukemia Biology, Department of Therapeutic Radiology-Radiation Oncology; Division of Hematology/Oncology/Bone Marrow Transplant Program, Department of Pediatrics; Department of Pharmacology, University of Minnesota, Minneapolis, MN; Department of Chemistry, Southwest Texas State University, San Marcos, TX; Chiron Corporation, Emeryville, CA, USA

Lisa M. Chelstrom Tumor Immunology Laboratory, Section of Cancer and Leukemia Biology, Department of Therapeutic Radiology-Radiation Oncology; Division of Hematology/Oncology/Bone Marrow Transplant Program, Department of Pediatrics; Department of Pharmacology, University of Minnesota, Minneapolis, MN; Department of Chemistry, Southwest Texas State University, San Marcos, TX; Chiron Corporation, Emeryville, CA, USA

L. L. Houston Tumor Immunology Laboratory, Section of Cancer and Leukemia Biology, Department of Therapeutic Radiology-Radiation Oncology; Division of Hematology/Oncology/Bone Marrow Transplant Program, Department of Pediatrics; Department of Pharmacology, University of Minnesota, Minneapolis, MN; Department of Chemistry, Southwest Texas State University, San Marcos, TX; Chiron Corporation, Emeryville, CA, USA

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Abstract

We have successfully constructed highly potent and selective anti-CD19 PAP immunotoxins using each of the three crosslinking agents, SPDP, LC-SPDP, or SMPT, to generate an intermolecular bridge between the B43 MoAb and PAP toxin moieties. These immunotoxins were selectively immunoreactive with and cytotoxic against CD19′ B-lineage ALL cells. In this report, we compared (a) in vivo chemical, immunological, and biological stability, (b) in uiuo immunogenicity, and (c) in vivo anti-leukemic activity of various B43-PAP immunotoxin constructs. Our data recommend the use of SPDP and SMPT rather than LC-SPDP for generation of B43(anti-CD19)-PAP immunotoxins as clinical anti-leukemic agents. To our knowledge, this is the first comparative analysis of the in vivo pharmacokinetic features, immunogenicity, and anti-leukemic activity of anti-CD19 PAP immunotoxins that were prepared with different heterobifunctional crosslinking agents.

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Effects of the Intermolecular Toxin-Monoclonal Antibody Linkage on the In Vivo Stability, Immunogenicity and Anti-Leukemic Activity of B43 (Anti-CD19) Pokeweed Antiviral Protein Immunotoxin

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Effects of the Intermolecular Toxin-Monoclonal Antibody Linkage on the In Vivo Stability, Immunogenicity and Anti-Leukemic Activity of B43 (Anti-CD19) Pokeweed Antiviral Protein Immunotoxin

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