Toxicity Profile of the Investigational New Biotherapeutic Agent, B43 (Anti-CD 19)-Pokeweed Antiviral Protein Immunotoxin

Abstract

The investigational biotherapeutic agent, B43(anti-CD19)-pokeweed antiviral protein (PAP) immunotoxin, has shown substantial anti-leukemic activity in SCID mouse models of human B-lineage leukemia and lymphoma. In this report, we describe the results of a comprehensive preclinical toxicity study which determined the toxicity profile of B43-PAP in BALB/c mice. Administration of unconjugated B43 monoclonal antibody was not associated with any toxicity, whereas B43-PAP caused dose-limiting and cardiac and renal toxicities which were fatal. In addition, B43-PAP also caused multifocal skeletal myofiber necrosis, which was associated with abnormal gait and lethargy. Notably, parenteral administrations of methylprednisolone, pentoxyphylline, or dopamine were able to markedly reduce B43-PAP related toxicity. This study provides a basis for further evaluation of the toxicity of B43-PAP in monkeys and humans.

Nanobody-Based Cancer Therapy of Solid Tumors

“…Although no nanobody-effector domain platform for cancer therapy has been characterized in vivo so far, pharmacokinetic toxicology studies of other immunotoxins, such as B43-pokeweed antiviral immunotoxin, have already showed dose-dependent kidney toxicity due to renal retention [63,64]. To avoid toxicity, renal retention of nanobody-drug conjugates should be minimized.…”

Expression and activity of a recombinant chimeric protein composed of pokeweed antiviral protein and of human interleukin‐2

“…PAP alone has a very low toxicity for eukaryotic cells, but conjugates made with PAP and a monoclonal antibody (mAb) are highly cytotoxic immunotoxins for cells bearing the mAbepitope [10][11][12][13]. In addition, PAP appeared to be a suitable ribosome-inactivating protein for the production of recombinant immunotoxins since an immunotoxin made with PAP remains cytotoxic when the linker used to bind the two pro-0014-5793/97/S17.00 © 1997 Federation of European Biochemical Societies.…”

“…PAP has been chemically linked to antibodies in order to specifically kill cells expressing the epitope recognized by the antibody part of the resulting immunotoxins, and clinical trials have been performed with a potent immunotoxin (B43-PAP) against B-lineage leukemia/lymphoma cells [10][11][12][13]. In addition, PAP appeared to be a suitable ribosome-inactivating protein for the production of recombinant cytotoxic fusion proteins [14].…”