Anti-CD123 Antibody-Drug Conjugates for Targeted Cancer Therapy

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Solution Overview

Problem

Current antibody-drug conjugates (ADCs) for cancer treatment, particularly those targeting KSP and CD123, face challenges in achieving effective apoptosis at low concentrations and providing long-lasting tumor inhibition.

Innovation Solution

Development of humanized anti-CD123 antibodies, such as TPP-8987, TPP-9476, TPP-8988, and TPP-9342, which are germlined and have specific CDR sequences, conjugated with cytotoxic agents via a linker, allowing for targeted delivery and release within tumor cells.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional chemotherapy is used to treat metastased tumors, then tumor growth is inhibited, but damage to normal tissue occurs and quality of life deteriorates

Engineering Contradiction:

Improvetumor inhibition efficacyVSAvoiddamage to normal tissue

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The chemotherapy approach is segmented into two distinct components: a targeting antibody that specifically binds to tumor-associated antigens (such as CD123, EGFR, or HER2) and a cytotoxic agent that is delivered only to tumor cells. This segmentation allows the cytotoxic effect to be localized to tumor cells while sparing normal tissue, resolving the contradiction between effective tumor inhibition and reduced damage to normal tissue.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

A linker molecule serves as an intermediary between the targeting antibody and the cytotoxic agent. This intermediary enables the controlled delivery and release of the cytotoxic payload specifically within tumor cells, ensuring that the harmful cytotoxic effect is mediated only where needed (in tumor cells) while protecting normal tissue from direct exposure.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If KSP inhibitors are used to achieve mitotic arrest and apoptosis, then tumor cell death is induced, but high concentrations are required and the duration of action is limited

Engineering Contradiction:

Improveapoptotic actionVSAvoidconcentration of KSP inhibitor

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The ADC system enables self-service delivery of the KSP inhibitor payload. The antibody component autonomously targets and binds to tumor cells expressing specific antigens, internalizes, and releases the cytotoxic payload directly within the tumor cell. This self-targeting mechanism ensures that the KSP inhibitor is delivered at sufficiently high local concentrations to induce mitotic arrest and apoptosis without requiring high systemic concentrations that would increase off-target toxicity.

Inventive Principle:

Principle #25Self-service

3Reliability

If ADCs with KSP inhibitors are developed, then selective tumor cell targeting is achieved, but the duration of tumor inhibition remains limited

Engineering Contradiction:

Improveselective tumor cell targetingVSAvoidduration of tumor inhibition

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The ADC design enables continuous useful action through sustained release of the cytotoxic payload. The antibody component provides stable and specific binding to tumor cells, ensuring continuous targeting. The linker is designed to release the cytotoxic agent continuously within the tumor cell, maintaining sustained intracellular concentrations that prolong the duration of mitotic arrest and apoptosis, thereby extending the duration of tumor inhibition while maintaining selective targeting.

Inventive Principle:

Principle #20Continuity of useful action

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

These ADCs demonstrate potent and long-lasting anti-tumor efficacy, inhibiting tumor growth with improved properties compared to existing ADCs, even at low concentrations, by selectively targeting CD123-expressing cancer cells.

Implementation Method 1

an internalising antibody directed against a tumour-associated antigen

Methodology Applied

Scientific EffectAntigen-antibody binding:

Implementation Method 2

Following introduction of the ADCs into the tumour cell and subsequent dissociation of the conjugate

Methodology Applied

Scientific EffectEndocytosis:

Data Source

PatentUS20230399411A1Specific antibody-drug-conjugates (ADCS) with KSP inhibitors and Anti-CD123-antibodies

Publication Date: 2023.12.14 BAYER PHARMA AG

AI summary

The invention relates to specific Antibody-Drug-Conjugates (ADCs) with KSP inhibitors and anti-CD123-antibodies, to the use of these conjugates for the treatment and/or prophylaxis of diseases and to the use of these conjugates for preparing medicaments for treatment and/or prevention of diseases, in particular hyperproliferative and/or angiogenic disorders such as, for example, cancer diseases. Such treatments can be carried out as monotherapy or else in combination with other medicaments or further therapeutic measures.