Humanized uPARAP Antibody-Drug Conjugates for Targeted Cytotoxic Delivery

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Solution Overview

Problem

Current cancer treatments using antibody-drug conjugates (ADCs) targeting uPARAP are inefficient and often cause adverse effects due to high dosing of therapeutic agents, necessitating the development of more potent and targeted therapies.

Innovation Solution

A humanized version of the murine 9b7 antibody, designated LC4HC3, is developed to create ADCs that specifically target uPARAP, enhancing efficacy through improved ligand affinity, internalization, and in vivo performance compared to existing ADCs.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Object-affected harmful factors

If traditional chemotherapeutic agents are used, then cancer cells are attacked, but healthy cells are severely affected causing adverse effects

Engineering Contradiction:

Improveadverse effects on healthy cellsVSAvoidtreatment efficiency

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The therapeutic agent is segmented into two components: a targeting antibody that specifically binds to uPARAP on cancer cells, and a cytotoxic drug payload. This segmentation allows the drug to be delivered only to target cells, reducing harm to healthy cells while maintaining treatment efficiency

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The antibody-drug conjugate uses the antibody as an intermediary carrier to transport the cytotoxic drug specifically to cancer cells expressing uPARAP. The antibody mediates selective delivery, ensuring the harmful drug only affects target cells and not healthy surrounding tissue

Inventive Principle:

Principle #24Intermediary (Mediator)

2Power

If high dosing of therapeutic agents is used, then treatment potency is increased, but adverse effects increase

Engineering Contradiction:

Improvetreatment potencyVSAvoidadverse effects

Core Design Contradiction:

PowerVSObject-affected harmful factors

Solution Approach 1:

The antibody is pre-conjugated to the cytotoxic drug at controlled ratios, creating a targeted delivery system before administration. This preliminary preparation ensures that high potency is achieved only at the target site, preventing systemic adverse effects from high dosing

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The high concentration of cytotoxic drug is localized specifically to cancer cells through antibody-mediated targeting. The drug exhibits high potency locally at the tumor site while maintaining low systemic concentration, thus achieving high treatment potency without proportional increase in adverse effects

Inventive Principle:

Principle #3Local quality

3Manufacturing precision

If ADCs with improved ligand affinity are developed, then tumor targeting is enhanced, but manufacturing complexity increases

Engineering Contradiction:

Improvetargeting precisionVSAvoidADC structure complexity

Core Design Contradiction:

Manufacturing precisionVSDevice complexity

Solution Approach 1:

The antibody sequence is optimized by modifying specific amino acid residues in the variable regions to enhance binding affinity to uPARAP. This parameter change at the molecular level improves targeting precision without fundamentally altering the overall ADC structure or manufacturing process

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS20250302977A1Antibody-drug conjugates comprising humanized antibodies targeting urokinase type plasminogen activator receptor associated protein (uparap)

Publication Date: 2025.10.02 RIGSHOSPITALET

AI summary

The present invention relates to humanized antibodies and molecular conjugates targeting Urokinase type plasminogen activator receptor associated protein (uPARAP), in particular antibody-drug conjugates (ADCs) comprising humanized antibodies directed against uPARAP and their use in delivery of active agents to cells and tissues expressing uPARAP. The invention further relates to the use of said ADCs in the treatment of diseases involving uPARAP expressing cells, such as certain cancers.