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Research ArticleBasic Science Investigations

188Re-ZHER2:V2, a Promising Affibody-Based Targeting Agent Against HER2-Expressing Tumors: Preclinical Assessment

Mohamed Altai, Helena Wållberg, Hadis Honarvar, Joanna Strand, Anna Orlova, Zohreh Varasteh, Mattias Sandström, John Löfblom, Erik Larsson, Sven-Erik Strand, Mark Lubberink, Stefan Ståhl and Vladimir Tolmachev
Journal of Nuclear Medicine November 2014, 55 (11) 1842-1848; DOI: https://doi.org/10.2967/jnumed.114.140194
Mohamed Altai
1Division of Biomedical Radiation Sciences, Uppsala University, Uppsala, Sweden
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Helena Wållberg
2Division of Protein Technology, School of Biotechnology, KTH Royal Institute of Technology, Stockholm, Sweden
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Hadis Honarvar
1Division of Biomedical Radiation Sciences, Uppsala University, Uppsala, Sweden
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Joanna Strand
1Division of Biomedical Radiation Sciences, Uppsala University, Uppsala, Sweden
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Anna Orlova
3Preclinical PET Platform, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden
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Zohreh Varasteh
3Preclinical PET Platform, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden
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Mattias Sandström
4Nuclear Medicine and PET, Uppsala University, Uppsala, Sweden
5Medical Physics, Uppsala University Hospital, Uppsala, Sweden; and
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John Löfblom
2Division of Protein Technology, School of Biotechnology, KTH Royal Institute of Technology, Stockholm, Sweden
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Erik Larsson
6Medical Radiation Physics, Clinical Sciences, Lund University, Lund, Sweden
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Sven-Erik Strand
6Medical Radiation Physics, Clinical Sciences, Lund University, Lund, Sweden
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Mark Lubberink
4Nuclear Medicine and PET, Uppsala University, Uppsala, Sweden
5Medical Physics, Uppsala University Hospital, Uppsala, Sweden; and
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Stefan Ståhl
2Division of Protein Technology, School of Biotechnology, KTH Royal Institute of Technology, Stockholm, Sweden
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Vladimir Tolmachev
1Division of Biomedical Radiation Sciences, Uppsala University, Uppsala, Sweden
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  • FIGURE 1.
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    FIGURE 1.

    Cell-associated radioactivity as function of time after interrupted incubation of SKOV-3 cells with 188Re-ZHER2:V2. Data are presented as average value from 3 cell dishes ± SD. Error bars might not be seen because they are smaller than point symbols.

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    FIGURE 2.

    In vivo binding specificity of 188Re-ZHER2:V2 in mice bearing ovarian cancer SKOV-3 xenografts at 4 h after injection. Blocked group was subcutaneously preinjected with excess amount of nonlabeled ZHER2:342. Results are presented as %IA/g.

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    FIGURE 3.

    Imaging of HER2 expression in SKOV-3 ovarian cancer xenografts (high HER2 expression) in NMRI nu/nu mice using 188Re-ZHER2:V2. Planar scintillation-camera images were acquired at 1 h (A) and 4 h (B) after injection. Arrows point to tumors (T) and kidneys (K).

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    FIGURE 4.

    Tumor-absorbed dose vs. mass for 188Re-ZHER2:V2.

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    TABLE 1

    Biodistribution of 188Re-ZHER2:V2 in NMRI nu/nu Mice Bearing HER2-Expressing SKOV-3 Xenografts

    Uptake
    Organ20 min1 h4 h8 h24 h48 h
    Blood3.0 ± 0.31.4 ± 0.10.3 ± 0.10.05 ± 0.020.02 ± 0.010.006 ± 0.003
    Heart1.4 ± 0.30.6 ± 0.10.11 ± 0.020.05 ± 0.010.02 ± 0.01NM
    Lung3.4 ± 0.21.7 ± 0.20.28 ± 0.050.08 ± 0.030.03 ± 0.01NM
    Salivary gland1.6 ± 0.51.1 ± 0.30.2 ± 0.10.06 ± 0.030.02 ± 0.01NM
    Thyroid*0.07 ± 0.020.04 ± 0.020.01 ± 0.0010.01 ± 0.0040.002 ± 0.001NM
    Liver3.4 ± 0.32.2 ± 0.20.51 ± 0.090.26 ± 0.060.12 ± 0.030.06 ± 0.016
    Spleen1.5 ± 0.20.87 ± 0.060.16 ± 0.020.08 ± 0.010.03 ± 0.01NM
    Pancreas0.8 ± 0.20.4 ± 0.10.08 ± 0.030.030 ± 0.0030.01 ± 0.01NM
    Stomach2.0 ± 0.081.3 ± 0.230.3 ± 0.10.08 ± 0.010.08 ± 0.07NM
    Small intestine1.4 ± 0.10.9 ± 0.20.16 ± 0.080.08 ± 0.070.04 ± 0.03NM
    Large intestine1.9 ± 0.081.2 ± 0.60.19 ± 0.050.3 ± 0.30.04 ± 0.010.02 ± 0.004
    Kidney47 ± 218 ± 32.1 ± 0.21.0 ± 0.20.51 ± 0.080.30 ± 0.12
    Tumor8.7 ± 0.914 ± 212 ± 28.0 ± 0.65 ± 21.8 ± 0.5
    Skin2.4 ± 0.41.4 ± 0.10.6 ± 0.50.10 ± 0.020.04 ± 0.020.02 ± 0.005
    Muscle0.6 ± 0.10.28 ± 0.030.06 ± 0.030.02 ± 0.010.02 ± 0.01NM
    Bone1.0 ± 0.10.6 ± 0.10.12 ± 0.010.05 ± 0.020.04 ± 0.02NM
    Brain0.08 ± 0.020.05 ± 0.010.020 ± 0.0030.01 ± 0.0010.01 ± 0.002NM
    Carcass*23 ± 214 ± 42 ± 11.1 ± 0.90.35 ± 0.090.19 ± 0.04
    • ↵* Data for thyroid and carcass are presented as %IA per whole sample.

    • NM = not measurable, below detection limit.

    • Uptake is expressed as %IA/g and presented as average value from 4 animals ± SD. Data are corrected for decay and self-attenuation in samples.

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    TABLE 2

    Calculated Absorbed Dose (Gy/MBq) for 188Re-ZHER2:V2 in Mice Using Murine Moby Phantom

    OrganSelf-doseTotal absorbed dose
    Blood0.0080.099
    Heart0.0030.094
    Lung0.0190.14
    Salivary gland0.00620.11
    Thyroid0.000220.13
    Liver0.0270.079
    Spleen0.00680.072
    Pancreas0.00240.075
    Stomach0.0140.061
    Small intestine0.00580.076
    Large intestine0.00510.11
    Kidney0.170.23
    Skin0.00380.081
    Bone0.00190.10
    Brain0.000730.026
    Carcass0.160.16
    Tumor 10.400.43
    Tumor 20.400.43
    Tumor 30.400.44
    Bone marrow0.00290.096
    • Tumors 1, 2, and 3 stand for tumors in right hind leg, left hind leg, and left flank, respectively.

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    TABLE 3

    Calculated Absorbed Dose (mGy/MBq) for 188Re-ZHER2:V2 in Humans Using OLINDA/EXM 1.0

    OrganAbsorbed dose, 188Re-ZHER2:V2
    Adrenals0.007
    Brain0.002
    Breasts0.006
    Gallbladder wall0.007
    Lower large intestine wall0.022 (0.046*)
    Small intestine0.018 (0.014*)
    Stomach wall0.007
    Upper large intestine wall0.034
    Heart wall0.006
    Kidneys0.189
    Liver0.029
    Lungs0.011
    Muscle0.006
    Ovaries0.007
    Pancreas0.006
    Red marrow0.010
    Osteogenic cells0.020
    Skin0.006
    Spleen0.009
    Thymus0.006
    Thyroid0.001
    Urinary bladder wall0.006
    Uterus0.007
    Total body0.009
    Tumor0.65
    • ↵* Using gastrointestinal tract model assuming 0.35% of injected dose entering small intestine.

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Journal of Nuclear Medicine: 55 (11)
Journal of Nuclear Medicine
Vol. 55, Issue 11
November 1, 2014
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188Re-ZHER2:V2, a Promising Affibody-Based Targeting Agent Against HER2-Expressing Tumors: Preclinical Assessment
Mohamed Altai, Helena Wållberg, Hadis Honarvar, Joanna Strand, Anna Orlova, Zohreh Varasteh, Mattias Sandström, John Löfblom, Erik Larsson, Sven-Erik Strand, Mark Lubberink, Stefan Ståhl, Vladimir Tolmachev
Journal of Nuclear Medicine Nov 2014, 55 (11) 1842-1848; DOI: 10.2967/jnumed.114.140194

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188Re-ZHER2:V2, a Promising Affibody-Based Targeting Agent Against HER2-Expressing Tumors: Preclinical Assessment
Mohamed Altai, Helena Wållberg, Hadis Honarvar, Joanna Strand, Anna Orlova, Zohreh Varasteh, Mattias Sandström, John Löfblom, Erik Larsson, Sven-Erik Strand, Mark Lubberink, Stefan Ståhl, Vladimir Tolmachev
Journal of Nuclear Medicine Nov 2014, 55 (11) 1842-1848; DOI: 10.2967/jnumed.114.140194
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