Rapid Generation of Murine Bispecific Antibodies Using FAST-IgTM for Preclinical Screening of HER2/CD3 T-Cell Engagers
Abstract
:1. Introduction
2. Materials and Methods
2.1. Preparation of FAST-Ig Antibodies
2.2. Antibody Homology Model Generation
2.3. Estimation of Percentage of BsAb by Mass Spectrometry
2.4. Estimation of Percentage of BsAb by Cation Exchange Chromatography
2.5. Surface Plasmon Resonance (SPR)
2.6. Size Exclusion Chromatography
2.7. Thermal Shift Assay (TSA)
2.8. Jurkat NFAT-Luciferase Reporter Cell Assay
2.9. SDS-PAGE
3. Results
3.1. Comparison of Mouse and Human Antibody Amino Acid Sequences and Structures at the FAST-Ig Mutation Positions in the HC/LC Interface
3.2. Application of V1+C19 to Anti-HER2/CD3 Bispecific Antibodies
3.3. Retention of Parental Physicochemical Properties in Mouse BsAbs with V1+C19
3.4. Comparative Analysis of Target-Dependent T Cell Activation by HER2/CD3 BsAbs
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Name | Antigen | CL | VH | VL |
---|---|---|---|---|
m4D5 [20] | HER2 | kappa | QVQLQQSGPELVKPGASLKLSCTASGFNIKDTYIHWVKQRPEQGLEWIGRIYPTNGYTRYDPKFQDKATITADTSSNTAYLQVSRLTSEDTAVYYCSRWGGDGFYAMDYWGQGASVTVSS | DIVMTQSHKFMSTSVGDRVSITCKASQDVNTAVAWYQQKPGHSPKLLIYSASFRYTGVPDRFTGSRSGTDFTFTISSVQAEDLAVYYCQQHYTTPPTFGGGTKVEIK |
m2C4 [21] | HER2 | kappa | EVQLQQSGPELVKPGTSVKISCKASGFTFTDYTMDWVKQSHGKSLEWIGDVNPNSGGSIYNQRFKGKASLTVDRSSRIVYMELRSLTFEDTAVYYCARNLGPSFYFDYWGQGTTLTVSS | DTVMTQSHKIMSTSVGDRVSITCKASQDVSIGVAWYQQRPGQSPKLLIYSASYRYTGVPDRFTGSGSGTDFTFTISSVQAEDLAVYYCQQYYIYPYTFGGGTKLEIK |
mOKT3 [22] | CD3 | kappa | QVQLQQSGAELARPGASVKMSCKASGYTFTRYTMHWVKQRPGQGLEWIGYINPSRGYTNYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYCLDYWGQGTTLTVSS | QIVLTQSPAIMSASPGEKVTMTCSASSSVSYMNWYQQKSGTSPKRWIYDTSKLASGVPAHFRGSGSGTSYSLTISGMEAEDAATYYCQQWSSNPFTFGSGTKLEIN |
mHIT3a [23] | CD3 | kappa | QVQLQESGAELARPGASVKMSCKASGYTFTRYTMHWVKQRPGQGLEWIGYINPSRGYTNYNQKFKDKATLTTDKSSSTAYMELTRLTSEDSAVYYCARYYDDHYCLDYWGQGTTVTVSS | DIELTQSPAIMSASPGEKVTMTCSASSSVSYMNWYQQKSGTSPKRWIYDTSKLASGVPARFSGSGSGTSYSLTISGMEAEDAATYYCQQWSSNPFTFGSGTKLELK |
m12F6 [24] | CD3 | kappa | QVQLQQSGAELARPGASVKMSCKASGYTFTSYTMHWVKQRPGQGLEWIGYINPSSGYTKYNQKFKDKATLTADKSSSTAYMQLSSLTSEDSAVYYCARWQDYDVYFDYWGQGTTLTVSS | QIVLSQSPAILSASPGEKVTMTCRASSSVSYMHWYQQKPGSSPKPWIYATSNLASGVPARFSGSGSGTSYSLTISRVEAEDAATYYCQQWSSNPPTFGGGTKLETK |
mSP34 [25] | CD3 | lambda | EVQLVESGGGLVQPKGSLKLSCAASGFTFNTYAMNWVRQAPGKGLEWVARIRSKYNNYATYYADSVKDRFTISRDDSQSILYLQMNNLKTEDTAMYYCVRHGNFGNSYVSWFAYWGQGTLVTVSA | QAVVTQESALTTSPGETVTLTCRSSTGAVTTSNYANWVQEKPDHLFTGLIGGTNKRAPGVPARFSGSLIGDKAALTITGAQTEDEAIYFCALWYSNLWVFGGGTKLTVL |
mUCHT1 [26] | CD3 | kappa | EVQLQQSGPELVKPGASMKISCKASGYSFTGYTMNWVKQSHGKNLEWMGLINPYKGVSTYNQKFKDKATLTVDKSSSTAYMELLSLTSEDSAVYYCARSGYYGDSDWYFDVWGQGTTLTVFS | DIQMTQTTSSLSASLGDRVTISCRASQDIRNYLNWYQQKPDGTVKLLIYYTSRLHSGVPSKFSGSGSGTDYSLTISNLEQEDIATYFCQQGNTLPWTFAGGTKLEIK |
Chain Name | V1+C19 Mutations [17] | |
---|---|---|
Anti-HER2 HC (H1) | VH | CH1 |
Q39K | K147/Q175K | |
Anti-HER2 LC (L1) | VL | CL |
Q38E | S131E/Q160E/T180E | |
Anti-CD3 HC (H2) | VH | CH1 |
Q39E | K147E/Q175E | |
Anti-CD3 LC (L2) | VL | CL |
Q38K (E38K) | S131K/L160K/T180K (T131K/E160K/T180K) |
Subclass | FAST-Ig | BsAb Yield (%) | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
m4D5/mOKT3 | m4D5/mHIT3a | m4D5/m12F6 | m4D5/mSP34 | m4D5/mUCHT1 | m2C4/mOKT3 | m2C4/mHIT3a | m2C4/m12F6 | m2C4/mSP34 | m2C4/mUCHT1 | ||
mIgG1 | - | 31.5 | 96.2 | 72.9 | 15.1 | 58.7 * | 51.1 | 98.2 | 49.0 | 56.0 | 21.9 * |
mIgG1 | V1+C19 | 100.0 | 94.5 | 100.0 | 100.0 | 100.0 * | 100.0 | 100.0 | 98.6 | 90.0 | 100.0 * |
mIgG2a | V1+C19 | 100.0 | 100.0 | 100.0 | 100.0 | 100.0 * | 81.0 ** | 100.0 | 100.0 | 100.0 | 100.0 * |
Subclass | FAST-Ig | KD (mol/L) | ||||||
---|---|---|---|---|---|---|---|---|
Anti-HER2 | Anti-CD3 | |||||||
m4D5 | m2C4 | mOKT3 | mHIT3a | m12F6 | mSP34 | mUCHT1 | ||
mIgG1 | - | 1.03 × 10−9 | 7.59 × 10−10 | 4.82 × 10−6 | 7.54 × 10−6 | 1.68 × 10−5 | 2.09 × 10−8 | 1.45 × 10−9 |
mIgG1 | V1+C19 | 1.27 × 10−9 | 7.84 × 10−10 | 4.48 × 10−6 | 8.32 × 10−6 | 1.61 × 10−5 | 5.69 × 10−8 | 1.32 × 10−9 |
mIgG2a | - | 1.14 × 10−9 | 1.08 × 10−9 | 6.58 × 10−6 | 1.04 × 10−5 | 1.67 × 10−5 | 1.60 × 10−8 | 1.02 × 10−9 |
mIgG2a | V1+C19 | 9.60 × 10−10 | 1.36 × 10−9 | 7.68 × 10−6 | 1.04 × 10−5 | 1.64 × 10−5 | 2.57 × 10−8 | 1.32 × 10−9 |
Subclass | FAST-Ig | Tm1 (°C) | ||||||
---|---|---|---|---|---|---|---|---|
Anti-HER2 | Anti-CD3 | |||||||
m4D5 | m2C4 | mOKT3 | mHIT3a | m12F6 | mSP34 | mUCHT1 | ||
mIgG1 | - | 72.6 | 75.6 | 75.6 | 73.2 | 76.2 | 67.2 | 75.0 |
mIgG1 | V1+C19 | 69.0 | 74.4 | 75.0 | 72.6 | 76.2 | 67.8 | 74.4 |
mIgG2a | - | 70.2 | 71.4 | 75.0 | 71.4 | 74.4 | 66.6 | 73.8 |
mIgG2a | V1+C19 | 64.2 | 67.8 | 73.8 | 70.2 | 73.2 | 63.0 | 70.8 |
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Koga, H.; Kuroi, H.; Hirano, R.; Hirayama, H.; Nabuchi, Y.; Kuramochi, T. Rapid Generation of Murine Bispecific Antibodies Using FAST-IgTM for Preclinical Screening of HER2/CD3 T-Cell Engagers. Antibodies 2024, 13, 3. https://doi.org/10.3390/antib13010003
Koga H, Kuroi H, Hirano R, Hirayama H, Nabuchi Y, Kuramochi T. Rapid Generation of Murine Bispecific Antibodies Using FAST-IgTM for Preclinical Screening of HER2/CD3 T-Cell Engagers. Antibodies. 2024; 13(1):3. https://doi.org/10.3390/antib13010003
Chicago/Turabian StyleKoga, Hikaru, Haruka Kuroi, Rena Hirano, Hiroyuki Hirayama, Yoshiaki Nabuchi, and Taichi Kuramochi. 2024. "Rapid Generation of Murine Bispecific Antibodies Using FAST-IgTM for Preclinical Screening of HER2/CD3 T-Cell Engagers" Antibodies 13, no. 1: 3. https://doi.org/10.3390/antib13010003