Theranostic pretargeted radioimmunotherapy of colorectal cancer xenografts in mice using picomolar affinity ⁸⁶Y- or ¹⁷⁷Lu-DOTA-Bn binding scFv C825/GPA33 IgG bispecific immunoconjugates

Eur J Nucl Med Mol Imaging. 2016 May;43(5):925-937. doi: 10.1007/s00259-015-3254-8. Epub 2015 Nov 24.

Abstract

Purpose: GPA33 is a colorectal cancer (CRC) antigen with unique retention properties after huA33-mediated tumor targeting. We tested a pretargeted radioimmunotherapy (PRIT) approach for CRC using a tetravalent bispecific antibody with dual specificity for GPA33 tumor antigen and DOTA-Bn-(radiolanthanide metal) complex.

Methods: PRIT was optimized in vivo by titrating sequential intravenous doses of huA33-C825, the dextran-based clearing agent, and the C825 haptens (177)Lu-or (86)Y-DOTA-Bn in mice bearing the SW1222 subcutaneous (s.c.) CRC xenograft model.

Results: Using optimized PRIT, therapeutic indices (TIs) for tumor radiation-absorbed dose of 73 (tumor/blood) and 12 (tumor/kidney) were achieved. Estimated absorbed doses (cGy/MBq) to tumor, blood, liver, spleen, and kidney for single-cycle PRIT were 65.8, 0.9 (TI 73), 6.3 (TI 10), 6.6 (TI 10), and 5.3 (TI 12), respectively. Two cycles of PRIT (66.6 or 111 MBq (177)Lu-DOTA-Bn) were safe and effective, with a complete response of established s.c. tumors (100 - 700 mm(3)) in nine of nine mice, with two mice alive without recurrence at >140 days. Tumor log kill in this model was estimated to be 2.1 - 3.0 based on time to 500-mm(3) tumor recurrence. In addition, PRIT dosimetry/diagnosis was performed by PET imaging of the positron-emitting DOTA hapten (86)Y-DOTA-Bn.

Conclusion: We have developed anti-GPA33 PRIT as a triple-step theranostic strategy for preclinical detection, dosimetry, and safe targeted radiotherapy of established human colorectal mouse xenografts.

Keywords: Bispecific antibodies; GPA33; Multistep targeting; Pretargeting; Radioimmunotherapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Bispecific / immunology
  • Antibodies, Bispecific / therapeutic use*
  • Antibody Affinity*
  • Colorectal Neoplasms / diagnostic imaging*
  • Colorectal Neoplasms / radiotherapy
  • Immunoconjugates / immunology
  • Immunoconjugates / therapeutic use*
  • Immunoglobulin G / immunology
  • Lutetium / therapeutic use
  • Membrane Glycoproteins / immunology*
  • Mice
  • Radioimmunotherapy*
  • Radiopharmaceuticals / immunology
  • Radiopharmaceuticals / therapeutic use*
  • Single-Chain Antibodies / immunology
  • Single-Chain Antibodies / therapeutic use
  • Xenograft Model Antitumor Assays
  • Yttrium Radioisotopes / therapeutic use

Substances

  • Antibodies, Bispecific
  • Gpa33 protein, mouse
  • Immunoconjugates
  • Immunoglobulin G
  • Membrane Glycoproteins
  • Radiopharmaceuticals
  • Single-Chain Antibodies
  • Yttrium Radioisotopes
  • Lutetium