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PLoS One. 2014 Jul 28;9(7):e103070. doi: 10.1371/journal.pone.0103070. eCollection 2014.

177Lu-DOTA-HH1, a novel anti-CD37 radio-immunoconjugate: a study of toxicity in nude mice.

Author information

1
Nordic Nanovector AS, Oslo, Norway; Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo, Norway.
2
Sciencons Ltd., Oslo, Norway.
3
Accelera Srl., Nerviano (Milano), Italy.
4
Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway; Institute for Clinical Medicine, University of Oslo, Oslo, Norway.
5
Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital, Montebello, Oslo, Norway.
6
Nordic Nanovector AS, Oslo, Norway.

Abstract

BACKGROUND:

CD37 is an internalizing B-cell antigen expressed on Non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia cells (CLL). The anti-CD37 monoclonal antibody HH1 was conjugated to the bifunctional chelator p-SCN-Bn-DOTA and labelled with the beta-particle emitting radionuclide 177Lu creating the radio-immunoconjugate (RIC) 177Lu-DOTA-HH1 (177Lu-HH1, trade name Betalutin). The present toxicity study was performed prior to initiation of clinical studies with 177Lu-HH1.

METHODOLOGY/PRINCIPAL FINDINGS:

Nude mice with or without tumor xenografts were treated with 50 to 1000 MBq/kg 177Lu- HH1 and followed for clinical signs of toxicity up to ten months. Acute, life threatening bone marrow toxicity was observed in animals receiving 800 and 1000 MBq/kg 177Lu-HH1. Significant changes in serum concentrations of liver enzymes were evident for treatment with 1000 MBq/kg 177Lu-HH1. Lymphoid depletion, liver necrosis and atrophy, and interstitial cell hyperplasia of the ovaries were also observed for mice in this dose group.

CONCLUSIONS/SIGNIFICANCE:

177Lu-DOTA-HH1 was well tolerated at dosages about 10 times above those considered relevant for radioimmunotherapy in patients with B-cell derived malignancies.The toxicity profile was as expected for RICs. Our experimental results have paved the way for clinical evaluation of 177Lu-HH1 in NHL patients.

PMID:
25068508
PMCID:
PMC4113375
DOI:
10.1371/journal.pone.0103070
[Indexed for MEDLINE]
Free PMC Article

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