Antibody-Conjugates for Trop-2 Targeting via Chemoenzymatic Glycan Conjugation
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Solution Overview
Problem
Current antibody-drug conjugates (ADCs) targeting Trop-2-expressing tumors face challenges in achieving site-specific conjugation and maintaining antibody stability, leading to heterogeneous mixtures and potential instability issues.
Innovation Solution
Development of antibody-conjugates with a specific linker and payload combination, utilizing a chemoenzymatic conjugation process through the glycan, to achieve site-specific targeting of Trop-2-expressing cells while enhancing the therapeutic index.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If conventional cysteine or lysine conjugation methods are used to attach payloads to antibodies, then the conjugation process is relatively simple and fast, but the resulting ADCs exhibit heterogeneous mixtures of positional isomers and reduced manufacturing precision
Solution Approach 1:
The patent applies preliminary action by introducing non-canonical amino acids (ncAAs) with unique reactive handles (ketone, acetylene, azide, cyclic alkyne, or cyclic alkene) into the antibody sequence at predetermined positions before conjugation. This pre-engineering of specific conjugation sites enables site-specific payload attachment, resolving the contradiction between manufacturing precision and process complexity by establishing a controlled foundation for subsequent conjugation reactions.
Solution Approach 2:
The patent implements local quality by incorporating ncAAs at specific positions within the antibody sequence (such as framework regions or CDRs) to create localized conjugation sites. This allows payload attachment at predetermined locations rather than distributed across multiple sites, achieving homogeneous ADC products with defined DAR values while maintaining the overall antibody structure and function.
2Manufacturing precision
If the natural antibody sequence is re-engineered to incorporate non-canonical amino acids for site-specific conjugation, then manufacturing precision and site-specific targeting are improved, but the process becomes time-consuming and costly
Solution Approach 1:
The patent uses non-canonical amino acids as intermediary molecules that bridge the antibody and payload. These ncAAs serve as universal handles that can be incorporated via established biochemical methods (such as orthogonal translation systems or enzymatic incorporation) and then react with corresponding payload moieties. This intermediary approach simplifies the overall manufacturing process by decoupling the protein expression step from the conjugation step, allowing each to be optimized independently.
Solution Approach 2:
The patent applies parameter changes by modifying the chemical properties of the antibody at specific positions through ncAA incorporation. The unique reactive handles of ncAAs (ketone, acetylene, azide, cyclic alkyne, or cyclic alkene) provide distinct chemical parameters that enable selective conjugation under mild conditions, improving manufacturing precision while allowing flexibility in conjugation chemistry selection to optimize ease of manufacture.
3Productivity
If conventional ADC conjugation methods are used, then the production process is faster and simpler, but the therapeutic index is reduced due to heterogeneous payload distribution
Solution Approach 1:
The patent applies preliminary action by pre-defining the number and position of ncAAs in the antibody sequence to achieve predetermined drug-to-antibody ratios (DAR). This pre-planning allows for controlled incorporation of payloads at specific sites, ensuring homogeneous distribution that improves therapeutic index while maintaining efficient production through standardized conjugation protocols.
Solution Approach 2:
The patent implements homogeneity by using ncAAs with unique reactive handles that enable selective and uniform payload attachment at predetermined positions. This results in ADC populations with consistent DAR values and uniform payload distribution, improving therapeutic reliability. The homogeneity is achieved while maintaining productivity through efficient conjugation reactions that proceed to high completion under optimized conditions.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The proposed antibody-conjugates demonstrate improved site-specific targeting and enhanced therapeutic efficacy against Trop-2-positive cancers, with a focus on increasing the therapeutic index by optimizing the conjugation process.
Implementation Method 1
Conjugation through the glycan by an oxidation-ligation sequence is known in the art
Implementation Method 2
Chemoenzymatic conjugation through the glycan is known in the art
Data Source
AI summary
The present invention concerns antibody-conjugates which are especially suitable for the targeting of Trop-2-expressing cells, in particular tumour cells. The antibody-conjugates according to the invention have structure (1):AB-[(L6)b-{Z-L-D}x]y (1)Herein, AB is an antibody capable of targeting Trop-2-expressing tumours; L is a linker that links Z to D; Z is a connecting group; L6 is -GlcNAc(Fuc)w-(G)j-S-(L7)w-, wherein G is a monosaccharide, j is an integer in the range of 0-10, S is a sugar or a sugar derivative, GlcNAc is N-acetylglucosamine and Fuc is fucose, w is 0 or 1, w′ is 0, 1 or 2 and L7 is —N(H)C(O)CH2—, —N(H)C(O)CF2— or —CH2—; D is exatecan; b is 0 or 1; x is 1 or 2; and y is 1, 2, 3 or 4. The invention further concerns a method for preparing the antibody-conjugates of structure (1) and application of the antibody-conjugates of structure (1).