Trop-2 Antibody Conjugates With Glycan Linking for Safer Payload Delivery
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Solution Overview
Problem
Current antibody-drug conjugates (ADCs) targeting Trop-2 for cancer treatment face challenges in terms of safety and efficacy, with existing methods being time-consuming, costly, and potentially leading to instability and modest antitumor activity.
Innovation Solution
The development of antibody-conjugates that utilize a specific mode of conjugation through the glycan of the antibody, linking highly toxic payloads to Trop-2-expressing cells, enhancing the therapeutic index by using linkers and connecting groups that improve safety and efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional antibody-drug conjugates are used to target Trop-2, then antitumor activity is achieved, but safety is compromised and therapeutic index is modest
Solution Approach 1:
The patent applies preliminary action by pre-conjugating multiple cytotoxic payloads to the antibody before administration. The antibody is prepared in advance with a controlled number of drug molecules attached (DDA of 2-8), ensuring that the therapeutic agent is ready for immediate targeted delivery to Trop-2-expressing tumors, thereby improving safety and therapeutic index
Solution Approach 2:
The patent employs parameter changes by optimizing the drug-to-antibody ratio (DDA) to a specific range of 2-8, which differs from conventional ADCs. This parameter optimization, along with controlling the polydispersity index (PDI) below 0.2, enhances the therapeutic index by balancing efficacy and safety
2Ease of manufacture
If conventional conjugation methods are used, then antibody-drug conjugates can be produced, but the process is time-consuming and costly
Solution Approach 1:
The patent uses preliminary action by pre-conjugating the drug payload to the antibody in a controlled manner before final formulation. This pre-conjugation step allows for optimization of the conjugation process under controlled conditions, reducing overall manufacturing time and cost while ensuring consistent quality
Solution Approach 2:
The patent applies parameter changes by optimizing conjugation conditions to achieve a specific drug-to-antibody ratio (DDA of 2-8) and low polydispersity index (PDI < 0.2). These parameter optimizations streamline the manufacturing process, making it more efficient and cost-effective
3Reliability
If conventional ADCs are administered, then treatment is provided, but stability is compromised leading to modest antitumor activity
Solution Approach 1:
The patent employs parameter changes by controlling the polydispersity index (PDI) to be less than 0.2 and maintaining a specific drug-to-antibody ratio (DDA of 2-8). These parameter controls ensure high stability of the ADC in circulation, preventing premature drug release and improving antitumor activity
Solution Approach 2:
The patent uses copying by creating a highly uniform and consistent ADC structure with low PDI. This uniformity ensures that each ADC molecule behaves predictably in the body, improving stability and therapeutic efficacy through consistent pharmacokinetic and pharmacodynamic properties
Data Source
AI summary
The present invention concerns antibody-conjugate having general structure (2):wherein AB is an antibody capable of targeting Trop-2-expressing tumours and D is selected from the group consisting of taxanes, anthracyclines, camptothecins, epothilones, mytomycins, combretastatins, vinca alkaloids, maytansinoids, enediynes such as calicheamicins, duocarmycins, tubulysins, amatoxins, bleomycins, dolastatins and auristatins, pyrrolobenzodiazepine dimers, indolinobenzodiazepine dimers, radioisotopes, therapeutic proteins and peptides (or fragments thereof), kinase inhibitors, MEK inhibitors, KSP inhibitors, and analogues or prodrugs thereof. These antibody-conjugates exhibit an improved therapeutic index. The invention further concerns a process for preparing the antibody-conjugate according to the invention, a method for targeting Trop-2-expressing cells, medical uses of the antibody-conjugates according to the invention.