Cleavable Molecular Scaffolds for Targeted Biologic Delivery
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Solution Overview
Problem
Current biologically active molecules, such as ADCs and nucleic acid-based therapeutics, face challenges with non-specificity, off-target effects, insufficient safety, efficacy, and poor accumulation at target sites, leading to adverse events and reduced therapeutic efficacy.
Innovation Solution
A molecular scaffold is developed for covalently binding biologically active molecules to carrier molecules, utilizing a polymeric or oligomeric structure with a cleavable bond for targeted delivery, enhancing specificity and safety by using saponins like SO1861 and QS-21, and incorporating a cleavable linker for endosomal escape.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If biologically active molecules are administered to achieve therapeutic effect, then therapeutic efficacy is improved, but off-target effects and adverse events increase
Solution Approach 1:
The biologically active molecule is segmented into two separate components: a targeting component (carrier molecule) and a therapeutic component (biologically active molecule). The carrier molecule specifically binds to target cells to deliver the therapeutic component, ensuring that the therapeutic effect is localized to the intended target and reducing off-target effects throughout the body.
Solution Approach 2:
A carrier molecule acts as an intermediary between the biologically active molecule and the target cell. The carrier molecule specifically recognizes and binds to target cells through antigen-antibody interactions, serving as a mediator that directs the therapeutic component to the correct location while protecting it from premature activation or degradation in circulation.
2Reliability
If high dose of biologically active molecule is administered to improve efficacy, then therapeutic effect is enhanced, but safety and tolerability deteriorate
Solution Approach 1:
By separating the therapeutic component from the targeting component, the system allows administration of high doses of the biologically active molecule without systemic toxicity. The carrier molecule ensures that high concentrations of the therapeutic component are delivered only to target cells, while non-target tissues are spared from exposure.
Solution Approach 2:
The therapeutic component exhibits local quality enhancement at the target site. Through specific binding of the carrier molecule to target cells, the biologically active molecule achieves high local concentration where needed, while maintaining low systemic concentration, thereby enhancing efficacy at the target without proportionally increasing systemic toxicity.
3Reliability
If biologically active molecule is administered to achieve therapeutic effect, then disease treatment is improved, but accumulation at target site is insufficient
Solution Approach 1:
The carrier molecule serves as a mediator that actively transports the biologically active molecule to the target site. Through specific binding interactions with target cell antigens, the carrier molecule concentrates the therapeutic component at the target site, overcoming the limitation of passive distribution and ensuring sufficient accumulation for effective treatment.
Solution Approach 2:
The carrier molecule performs preliminary action by specifically recognizing and binding to target cells before releasing the therapeutic component. This preliminary targeting action ensures that the biologically active molecule is delivered to the correct location and accumulates at sufficient concentrations before exerting its therapeutic effect.
4Reliability
If conventional ADC structure is used, then targeted delivery is achieved, but therapeutic window remains limited
Solution Approach 1:
The system enhances local quality at the target site by using a carrier molecule that specifically binds to target cells. This specific binding creates a high local concentration of the biologically active molecule at the target site while maintaining low systemic levels, thereby significantly widening the therapeutic window through selective localization.
Solution Approach 2:
The system changes the concentration parameter distribution of the biologically active molecule from uniform systemic distribution to highly localized concentration at the target site. This parameter change in spatial distribution allows administration of higher doses to achieve better efficacy while maintaining safety, thereby expanding the therapeutic window.
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 scaffold improves targeted delivery, reducing off-target effects and enhancing therapeutic efficacy by ensuring timely and sustained action at the target site, addressing the limitations of existing drug delivery systems.
Implementation Method 1
utilizing a polymeric or oligomeric structure with a cleavable bond for targeted delivery
Data Source
Figure 1
Figure 2~3A
Figure 3B~3C
AI summary
The invention relates to a molecular scaffold suitable for covalently binding at least one biologically active molecule to a carrier molecule, the scaffold comprising a polymeric structure and the biologically active molecules covalently bound to said polymeric structure, and wherein the scaffold further comprises a chemical group for covalently coupling of the scaffold to the carrier molecule. The biologically active molecule has a molecular weight of 3.000 Dalton or less, such as 1.700 Dalton - 1.950 Dalton. The biologically active molecule is an amphiphilic molecule in some embodiments. The biologically active molecule is a single specific molecule or is a mixture of different types of molecules, when more than one biologically active molecules are covalently bound to the polymeric (or oligomeric) structure. In particular, the invention relates to monoclonal antibody-based antibody-drug conjugates with improved therapeutic window of the drug due to covalent linkage of (a cluster of) potentiator molecules, e.g. a payload such as a protein toxin or oligonucleotide to the ADC, or alternatively, due to co-administration of an ADC and a cell-targeting conjugate comprising (a cluster of) potentiator molecules to a patient in need thereof. The invention also relates to a method for producing a scaffold suitable for covalently binding a biologically active molecule to a carrier molecule, providing a cluster of potentiator molecules. Furthermore, the invention relates to a method for producing a scaffold covalently bound to a carrier molecule, the scaffold comprising a covalently bound biologically active molecule, the carrier molecule comprising an antibody and a payload.