Antitumor antagonists
An antagonist, anti-tumor technology, applied in the direction of anti-tumor drugs, antibodies, antibody mimics/scaffolds, etc., can solve problems such as drug resistance of antibodies
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example 1
[0340] Example 1: Generation of Monoclonal Antibodies
[0341] The monoclonal antibodies (mAbs) of the present application are generated and screened using techniques well known in the art, see eg, Harlowand Lane (1988). Antibodies, A Laboratory Manual, Cold Spring Harbor Publications, New York. Antigen-specific hybridoma mAbs were cloned, sequenced and engineered using techniques well known in the art, see eg, Lo.B.K.C Methods in Molecular Biology TM .Volume 248 2004. Antibody Engineering.
example 2
[0342] Example 2: Design of Bispecific Antitumor Antagonists
[0343] Figure 5A and 5B Two bispecific antitumor antagonists, Bi-PB-1 (or Bi-PLB-1) and Bi-PB-1 (or Bi-PLB-2), are shown separately. These antagonists comprise a checkpoint regulatory antibody backbone (anti-PD-1 or anti-PD-L1) and a TGF-β1 RII extracellular domain (TGF-β-RII ECD): (i) fused to each of the two heavy chains The carboxy terminus of the CH3 region in ( Figure 5A ) or (ii) inserted into the CH3 region of the Fc loop 5B).
[0344] exist Figure 5A and 5B In the embodiment shown in , the bispecific antibody may have an IgGl or IgG4 backbone. Furthermore, any one or more of the antibody specificities can be replaced by any other checkpoint modulator antagonist specificity and / or any tumor targeting antibody specificity, eg CD20, EGFR, etc.
[0345] Image 6 shows corresponding to Figure 5A and 5B Exemplary functional domain sequences of bispecific antibodies in .
[0346] Figure 7 A to Fig...
example 3
[0347] Example 3: Design of other bispecific antagonists
[0348] Figures 8A-8C Three different bispecific antagonists, Bi-AB-1, Bi-AlB-1 and Bi- , of the carboxy-terminal TGF-β1 RII extracellular domain (ECD) contained in mutant IgG1 (K447A) scaffolds, respectively, are shown Design of the ZB-1. Both Bi-AB-1 and Bi-AlB-1 contain amino-terminal anti-VEGF variable regions (VH1, VL1) from Avastin / bevacizumab; Bi-AlB-1 contains two amino acid substitutions in the VH region (E6Q , LIV). Bi-ZB-1 contains an amino-terminal afepricy domain upstream of the IgG1 Fc (K447A) region. In other embodiments, instead of a mutant IgG1 (K447A) scaffold, the bispecific antagonist comprises a wild-type IgG1 scaffold, a different mutant IgG1 scaffold, an IgG2 scaffold, a mutant IgG2 scaffold, an IgG4 scaffold, or a mutant IgG4 scaffold.
[0349] Figure 9A and 9B shows corresponding to Figures 8A-8C Various functional domain sequences of bispecific antagonists shown in .
[0350] Figur...
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