Tyrosinase-mediated protein site-specific conjugation and use thereof
AssigneesShanghai Shengdi Pharmaceutical Co., Ltd., Jiangsu Hengrui Pharmaceuticals Co., Ltd.
InventorsWei ZHANG, Mengxin QIAN, Xiaojing YUAN, Luyao BAO, Wenming REN, Cheng LIAO
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Abstract
The present disclosure relates to tyrosinase-mediated protein site-specific conjugation and a use thereof. Specifically, the present disclosure provides tyrosinase-mediated protein site-specific conjugation and a use thereof in the preparation of a drug (for example, an ADC).
Claims59
A conjugate, comprising a structure represented by formula I or a pharmaceutically acceptable salt thereof:
- wherein:
- Pc is a protein comprising an antibody constant region or a fragment thereof;
- L is a linker covalently linking Pc to D, and L is linked to an engineered tyrosine (Tyr) residue in the antibody constant region or the fragment thereof;
- the engineered tyrosine residue is not located near a N-glycosylation site, and Pc does not require removal/reduction of glycosylation modification before reacting with tyrosinase;
- D is a payload;
- x is 1 to 20;
- y is 1 to 20.
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A conjugate, comprising a structure represented by formula I or a pharmaceutically acceptable salt thereof:
- wherein:
- Pc is a protein comprising an antibody constant region or a fragment thereof;
- L is a linker covalently linking Pc to D, and L is linked to an engineered tyrosine residue in the antibody constant region or the fragment thereof;
- the engineered tyrosine residue is located at any one or any combination of positions 135, 137, 192, 223, and 329 of a heavy chain HC and position 202 of a light chain LC of Pc, wherein the amino acid residue positions are defined according to the EU numbering scheme;
- D is a payload;
- x is 1 to 20;
- y is 1 to 20.
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A protein, comprising an antibody constant region or a fragment thereof, wherein:
- (a) the antibody constant region or the fragment thereof comprises one or more engineered tyrosine residues, and the phenol moieties of the engineered tyrosine residues are oxidizable by monomeric tyrosinase to o-quinone moieties but are not oxidizable by multimeric tyrosinase to o-quinone moieties, or
- (b) the antibody constant region or the fragment thereof comprises one or more engineered tyrosine residues, and the engineered tyrosine residues are located at any one or any combination of positions 135, 137, 192, 223, and 329 of a heavy chain HC and position 202 of a light chain LC optionally, the monomeric tyrosinase is derived from Bacillus megaterium or Verrucomicrobium spinosum;
- the multimeric tyrosinase is a tetrameric enzyme, and the tetrameric enzyme is preferably derived from a mushroom.
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-46. (canceled)
Dependencies are inferred from the claim text.