Human microtubule-associated protein tau mediates targeted killing of CD30(+) lymphoma cells in vitro and inhibits tumour growth in vivo.

Abstract

Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (sALCL) are rare lymphoproliferative cancer types. Although most HL patients can be cured by chemo- and radio-therapy, 4-50% of patients relapse and have a poor prognosis. The need for improved therapeutic options for patients with relapsed or refractory disease has been addressed by CD30-specific antibody-based immunotherapeutics. However, available CD30-specific monoclonal antibodies (mAbs), antibody drug conjugates (ADCs) or chimeric immunotoxins suffer from the requirement of a functional host immunity, undesirable immune reactions or heterogeneity and instability, respectively. Here, we present a new fusion protein comprised of the CD30-specific antibody single-chain fragment Ki4(scFv) and the human pro-apoptotic effector protein, microtubule-associated protein tau (MAPT). Ki4(scFv)-MAP selectively induced apoptosis in rapidly proliferating L540cy, L428, and Karpas 299 cells in a dose-dependent manner. Tubulin polymerization assays confirmed that Ki4(scFv)-MAP stabilizes microtubules, suggesting a mechanism for its pro-apoptotic action. Dose-finding experiments proved that Ki4(scFv)-MAP is well tolerated in mice compared to the previously reported Ki4(scFv)-ETA'. Ki4(scFv)-MAP significantly inhibited growth of subcutaneous L540cy xenograft tumours in mice. Our data present a novel approach for the treatment of CD30(+) lymphomas, combining the binding specificity of a target-specific antibody fragment with the selective cytotoxicity of MAPT towards proliferating lymphoma cells.

• Authors: Dmitrij Hristodorov, Johannes Nordlohne, Radoslav Mladenov, Michael Huhn, Rainer Fischer, Theo Thepen, Stefan Barth
• Journal: British journal of haematology (Br J Haematol) Vol. 164 Issue 2 Pg. 251-7 (Jan 2014) ISSN: 1365-2141 [Electronic] England
• PMID: 24164493 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 John Wiley & Sons Ltd.

Chemical References

• Ki-1 Antigen
• Recombinant Fusion Proteins
• Single-Chain Antibodies
• tau Proteins

Topics

• Animals
• Antibody-Dependent Cell Cytotoxicity
• Apoptosis (drug effects)
• Cell Line, Tumor
• Disease Models, Animal
• Female
• Hodgkin Disease (metabolism, pathology)
• Humans
• Ki-1 Antigen (immunology, metabolism)
• Mice
• Microtubules (metabolism)
• Protein Binding
• Protein Stability
• Recombinant Fusion Proteins (immunology, metabolism, pharmacology)
• Single-Chain Antibodies (immunology, metabolism, pharmacology)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays
• tau Proteins (immunology, metabolism)