Evaluation of Radiolabeled Girentuximab In Vitro and In Vivo
Abstract
:1. Introduction
2. Results
2.1. Conjugation of p-SCN-βn-DOTA to cG250
2.2. Identification of DOTA Modification Sites
2.3. Ratio of DOTA Molecules Per Molecule of Antibody
2.4. In Vitro Characterization of the Conjugates
2.5. Radiochemical Purity and Influence of Sodium Ascorbate on the Stability In Vitro
2.6. In Vitro Radioimmunoreactivity of the Conjugates Labeled with 177Lu
2.7. Biodistribution
2.8. Effect of Tumor Volume, Hypoxia, and Necrosis on cG250 Tumor Retention
3. Discussion
4. Materials and Methods
4.1. Preparation of cG250 Conjugates
4.2. Characterization by Mass Spectrometry
4.3. Cell Culture
4.4. Flow Cytometric Analysis
4.5. Radiolabeling, Quality Control, and Radiostability
4.6. Radioactivity Binding Assay
4.7. Animals
4.8. Immunohistochemical Analysis (IHC)
4.9. Biodistribution
4.10. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
Ab | antibody |
ADC | antibody drug conjugate |
Asn, N | asparagine amino residues |
BM | biomolecule |
BFC | bifunctional chelator |
BSA | bovine serum albumin |
CAIX | carbonic anhydrase IX |
cG250 | monoclonal antibody anti-CAIX, girentuximab |
Cys, C | cysteine amino residues |
CDR | complementarity-determining regions |
CHCA | hydroxycinnamic acid |
CD31 | cluster of differentiation 31, endotelial cells marker |
DOTA | tetraxetan or 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid |
DOTA(SCN) | p-SCN-Bn-DOTA or S-2-(4-Isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid |
DTPA | pentetic acid or diethylenetriaminepentaacetic acid |
DTT | dithiothreitol |
DCB | Department of Chemistry and Biochemistry, University of Bern, Switzerland |
DBMR | Department for Biomedical Research, University of Bern, Switzerland |
d | day |
EDTA | ethylenediaminetetraacetic acid |
ESI | electrospray ionization |
FDR | false discovery rate |
FFPE | formalin-fixed paraffin-embedded |
FACS | fluorescence-activated cell sorting applied in flow cytometry |
FCS | fetal calf serum |
FT | Fourier transform |
Fac | formic acid |
Gln, Q | glutamine amino residues |
HC | heavy chain of immunoglobulin |
HIF-1 | hypoxia-inducible factor 1 |
HSA | human serum albumin |
HS | human serum |
HNSCC | head and neck squamous cell carcinomas (HNSCC) |
h | hour |
HPLC | high-performance liquid chromatography |
Ig | immunoglobulin |
IC50 | concentration of an inhibitor where the response (or binding) is reduced by half |
IHC | immunohistochemistry |
ICC | immunocytochemistry |
ITLC | instant thin layer chromatography |
ID | injected dose |
i.v. | intravenously |
LET | linear energy transfer |
LC | light chain of immunoglobulin |
LC | liquid chromatography |
Lys, K | lysine amino residues |
LRC | Laboratory of Radiochemistry, Paul Scherrer Institute, Villigen PSI, Switzerland |
mAb | monoclonal antibody |
MBq | megabecquerel |
Met, M | methionine amino residues |
MALDI | matrix assisted laser desorption/ionization–mass spectrometry |
MS | mass spectrometry |
MW | molecular weight or mass |
mgf | mascot generic file format |
MSKCC | Memorial Sloan Kettering Cancer Centre, New York, USA |
min | minute |
NaAsc | sodium ascorbate |
NaCl | saline solution |
NHL | non-Hodgkin’s lymphoma |
NHS | N-hydroxysuccinimide |
OCT | optimum cutting temperature |
PKM | pharmacokinetic modifying linker |
PK | pharmacokinetics |
PET | positron emission tomography |
PBS | phosphate buffer saline |
ppm | parts per million (chemical shift) |
PSI | Paul Scherrer Institute, Villigen PSI, Switzerland |
PKI | Institute of Pharmacology, University of Bern, Switzerland |
RIT | radioimmunotherapy |
RCCs | renal cell carcinomas |
RCP | radiochemical purity |
Rf | retardation factor |
RPMI | Roswell Park Memorial Institute medium |
RPM | revolutions per minute |
SEC | size exclusion chromatography |
SDS-PAGE | sodium dodecyl sulfate polyacrylamide gel electrophoresis |
SCN | isothiocyanate |
SG | silica gel |
t1/2 | half-life |
Tyr,Y | tyrosine amino residues |
TOF | time of flight |
TFA | trifluoroacetic acid |
TRU | Translational Research Unit, University of Bern, Switzerland |
Tris | hydroxymethylaminomethane |
UV | ultraviolet |
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Conjugate | MW (Da) | Ratio Non Reduced | Ratio Reduced | |
---|---|---|---|---|
HC | LC | |||
C2 (90 min) | - | - | 12–23 1 | 6–7 1 |
C3 (60 min) | 154,187.07 | 8–10 | 3–4 | 1–2 |
C7 (30 min) | 151,543.63 | 5–6 | 1–2 | 1–2 |
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Basaco, T.; Pektor, S.; Bermudez, J.M.; Meneses, N.; Heller, M.; Galván, J.A.; Boligán, K.F.; Schürch, S.; Von Gunten, S.; Türler, A.; et al. Evaluation of Radiolabeled Girentuximab In Vitro and In Vivo. Pharmaceuticals 2018, 11, 132. https://doi.org/10.3390/ph11040132
Basaco T, Pektor S, Bermudez JM, Meneses N, Heller M, Galván JA, Boligán KF, Schürch S, Von Gunten S, Türler A, et al. Evaluation of Radiolabeled Girentuximab In Vitro and In Vivo. Pharmaceuticals. 2018; 11(4):132. https://doi.org/10.3390/ph11040132
Chicago/Turabian StyleBasaco, Tais, Stefanie Pektor, Josue M. Bermudez, Niurka Meneses, Manfred Heller, José A. Galván, Kayluz F. Boligán, Stefan Schürch, Stephan Von Gunten, Andreas Türler, and et al. 2018. "Evaluation of Radiolabeled Girentuximab In Vitro and In Vivo" Pharmaceuticals 11, no. 4: 132. https://doi.org/10.3390/ph11040132