CdtB-LF Chimeric Toxin for Targeted Cell Delivery

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Solution Overview

Problem

The delivery of cytolethal distending toxin subunit B (CdtB) to target cells is inefficient, limiting its cytotoxic effects against undesirable cells such as cancer cells.

Innovation Solution

Conjugating or fusing CdtB with Bacillus anthracis toxin lethal factor (LF) to facilitate its entry into cells, utilizing protective antigen (PA) for translocation, and potentially incorporating a targeting moiety for specific cell delivery.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If CdtB is used alone to treat target cells, then it can destroy or inhibit the growth of undesirable cells, but its delivery to the interior of the cell is inefficient, lessening the cytotoxic effects

Engineering Contradiction:

Improvecytotoxic effectivenessVSAvoiddelivery efficiency

Core Design Contradiction:

ReliabilityVSEase of manufacture

Solution Approach 1:

The patent combines CdtB with Bacillus anthracis toxin lethal factor (LF) to create a chimeric molecule. The LF component provides efficient cellular entry capabilities through its interaction with protective antigen (PA), while CdtB provides the cytotoxic activity. This merging resolves the contradiction by delivering CdtB effectively into target cells through the LF-mediated entry mechanism, thereby improving both delivery efficiency and cytotoxic effectiveness.

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The patent uses protective antigen (PA) as an intermediary to facilitate the delivery of the CdtB-LF chimeric molecule into target cells. PA binds to cell surface receptors and enables the translocation of the chimeric molecule across the cell membrane. This intermediary mechanism resolves the delivery inefficiency problem while maintaining the cytotoxic effectiveness of CdtB against target cells.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If higher dosages of CdtB are used to overcome inefficient delivery, then cytotoxic effects may be improved, but systemic toxicity increases

Engineering Contradiction:

Improvecytotoxic effectivenessVSAvoidsystemic toxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent employs protective antigen (PA) and lethal factor (LF) as mediators to deliver CdtB specifically into target cells. This targeted delivery mechanism ensures that CdtB is released primarily at the site of action, reducing systemic circulation and associated toxicity. The chimeric molecule structure with cell-penetrating capabilities allows effective cytotoxic action at lower dosages while minimizing harmful systemic effects.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent creates a localized delivery system where the CdtB-LF chimeric molecule is delivered specifically to target cells through the LF-PA interaction mechanism. This local quality approach concentrates the cytotoxic effect at the intended site while reducing exposure of healthy tissues to CdtB, thereby improving the therapeutic index by reducing systemic toxicity.

Inventive Principle:

Principle #3Local quality

Data Source

PatentUS9890369B2Cytolethal distending toxin subunit B conjugated or fused to <i>Bacillus anthracis </i>toxin lethal factor

Publication Date: 2018.02.13 THE GOVERNMENT OF THE UNITED STATES OF AMERICA AS REPRESENTED BY THE SECRETARY DEPARTMENT OF HEALTH & HUMAN SERVICES

AI summary

Disclosed is a protein comprising a cytolethal distending toxin subunit B (CdtB) conjugated or fused to a Bacillus anthracis toxin lethal factor (LF) or a functional portion of LF. Related chimeric molecules, as well as related nucleic acids, recombinant expression vectors, host cells, populations of cells, pharmaceutical compositions, methods of treating or preventing cancer, and methods of inhibiting the growth of a target cell are also disclosed.