Preclinical evaluation of a diabody-based (177)Lu-radioimmunoconjugate for CD22-directed radioimmunotherapy in a non-Hodgkin lymphoma mouse model

Cancer Lett. 2016 Oct 28;381(2):296-304. doi: 10.1016/j.canlet.2016.08.007. Epub 2016 Aug 11.

Abstract

Radioimmunotherapy is considered as treatment option in recurrent and/or refractory B-cell non-Hodgkin lymphoma (B-NHL). To overcome the dose limiting bone marrow toxicity of IgG-based radioimmunoconjugates (RICs), we modified a humanized diabody with 5-, 10-, or 20-kDa polyethylene glycol (PEG) for CD22-targeted radioimmunotherapy using the low-energy β-emitter lutetium-177 ((177)Lu). A favorable pharmacokinetic profile was observed for the 10-kDa-PEG-diabody in nude mice being xenografted with subcutaneous human Burkitt lymphoma. Even at high doses of 16 MBq this diabody RIC was well tolerated by NOD Rag1(null) IL2rγ(null) (NRG) mice and did not reveal signs of organ long-term toxicity 80 days post injection. Combination therapy of the diabody RIC with unconjugated anti-CD20 Rituximab demonstrated therapeutic efficacy in established disseminated mantle cell lymphoma xenograft models. When compared with the combination of the IgG formatted (177)Lu anti-CD22 antibody and Rituximab, dual targeted therapy with the diabody RIC achieved an improved reduction of disease burden in the first nine days following treatment. The data indicate that the PEGylated anti-CD22 diabody may have potential for extending the repertoire of radiopharmaceuticals for the treatment of patients with B-NHL.

Keywords: CD22; Diabody; Dual-targeting; Lymphoma; PEGylation; Radioimmunotherapy.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Bispecific / immunology
  • Antibodies, Bispecific / pharmacokinetics
  • Antibodies, Bispecific / pharmacology*
  • Antibodies, Bispecific / toxicity
  • Antibodies, Monoclonal, Humanized / immunology
  • Antibodies, Monoclonal, Humanized / pharmacokinetics
  • Antibodies, Monoclonal, Humanized / pharmacology*
  • Antibodies, Monoclonal, Humanized / toxicity
  • Burkitt Lymphoma / immunology
  • Burkitt Lymphoma / metabolism
  • Burkitt Lymphoma / pathology
  • Burkitt Lymphoma / radiotherapy*
  • Cell Line, Tumor
  • Female
  • Forkhead Transcription Factors / deficiency
  • Forkhead Transcription Factors / genetics
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Immunoconjugates / pharmacokinetics
  • Immunoconjugates / pharmacology*
  • Immunoconjugates / toxicity
  • Immunoglobulins, Intravenous / pharmacology
  • Interleukin Receptor Common gamma Subunit / deficiency
  • Interleukin Receptor Common gamma Subunit / genetics
  • Lutetium / pharmacokinetics
  • Lutetium / pharmacology*
  • Lutetium / toxicity
  • Lymphoma, Mantle-Cell / immunology
  • Lymphoma, Mantle-Cell / metabolism
  • Lymphoma, Mantle-Cell / pathology
  • Lymphoma, Mantle-Cell / radiotherapy*
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, Nude
  • Radioimmunotherapy / adverse effects
  • Radioimmunotherapy / methods*
  • Radioisotopes / pharmacokinetics
  • Radioisotopes / pharmacology*
  • Radioisotopes / toxicity
  • Rituximab / pharmacology
  • Sialic Acid Binding Ig-like Lectin 2 / immunology*
  • Sialic Acid Binding Ig-like Lectin 2 / metabolism
  • Tissue Distribution
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies, Bispecific
  • Antibodies, Monoclonal, Humanized
  • CD22 protein, human
  • Forkhead Transcription Factors
  • Homeodomain Proteins
  • Il2rg protein, mouse
  • Immunoconjugates
  • Immunoglobulins, Intravenous
  • Interleukin Receptor Common gamma Subunit
  • Radioisotopes
  • Sialic Acid Binding Ig-like Lectin 2
  • Whn protein
  • RAG-1 protein
  • Rituximab
  • Lutetium