Hemiasterlin Derivative Antibody-Drug Conjugate Selective Toxicity

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Solution Overview

Problem

Hemiasterlin derivatives used in antibody-drug conjugates exhibit strong cytotoxicity to both target and normal cells, leading to unwanted side effects due to their non-specific cellular damage.

Innovation Solution

Development of a hemiasterlin derivative represented by specific formulas, which form antibody-drug conjugates that exhibit strong antitumor activity while minimizing cytotoxicity to normal cells by modifying the compound structure to reduce cell membrane permeability, thereby targeting antigen-expressing cells specifically.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If hemiasterlin derivatives are used in antibody-drug conjugates, then strong cytotoxic activity against target cells is achieved, but cytotoxicity to normal cells increases causing side effects

Engineering Contradiction:

Improveantitumor activityVSAvoidcytotoxicity to normal cells

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by modifying specific regions of the hemiasterlin molecule - introducing polar groups (carboxyl, hydroxyl, amino groups) at strategic positions to reduce membrane permeability locally, while preserving the core cytotoxic mechanism against cancer cells. This localized modification achieves selective toxicity reduction without compromising antitumor efficacy

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent systematically changes chemical parameters of the hemiasterlin derivative by varying substituents (R1-R6 groups) including carboxyl, hydroxyl, amino groups and their positions. These parameter changes reduce cell membrane permeability and thereby decrease cytotoxicity to normal cells while maintaining therapeutic effectiveness against tumor cells

Inventive Principle:

Principle #35Parameter changes

2Object-affected harmful factors

If hemiasterlin derivative structure is modified to reduce cell membrane permeability, then cytotoxicity to normal cells is reduced, but antitumor activity may be compromised

Engineering Contradiction:

Improvecytotoxicity to normal cellsVSAvoidantitumor activity

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The patent carefully adjusts chemical parameters by introducing specific polar substituents (carboxyl, hydroxyl, amino groups) at optimized positions and concentrations. These parameter changes reduce membrane permeability to minimize normal cell toxicity while the antibody targeting ensures sufficient drug delivery to tumor cells to maintain antitumor activity

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent uses the antibody as an intermediary that compensates for reduced drug permeability. The antibody-drug conjugate ensures targeted delivery to tumor cells, overcoming the reduced intrinsic permeability of the modified hemiasterlin derivative and maintaining therapeutic efficacy

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS12018093B2Hemiasterlin derivatives and antibody-drug conjugates including same

Publication Date: 2024.06.25 SUMITOMO PHARMA CO LTD

AI summary

A compound represented by formula (1):whereinAA represents a particular amino acid residue or a C1-6 alkyl ester thereof, and when there is a plurality of AAs, each AA may be the same as or different from each other and AAs are bonded to each other via an amide bond;an N-terminal nitrogen atom of (AA)m forms an amide bond together with carbonyl (a);Q represents an unsubstituted phenyl group, or a group represented by formula (Q-1), formula (Qa-2), formula (Qa-3), formula (Qa-4), formula (Qa-5), formula (Qa-6) or formula (Qa-7);R1a and R1b each independently represent a hydrogen atom or a C1-6 alkyl group; andm represents an integer of 1 to 10,or a salt thereof.