CD22 Crosslinking Triggers Apoptosis in Hematopoietic Cancer

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Solution Overview

Problem

Current anti-CD22 antibodies, such as epratuzumab, while effective in treating hematopoietic cancers and autoimmune diseases, have limited understanding of their mechanism of action and require improved methods for enhanced efficacy and reduced toxicity.

Innovation Solution

The use of antibodies that extensively cross-link CD22 on B cells, inducing phosphorylation of CD22, CD79a and CD79b, translocation to lipid rafts, stabilization of F-actin, and generation of reactive oxygen species, leading to caspase-dependent apoptosis, and trogocytosis of BCR-related antigens, thereby treating hematopoietic cancer and autoimmune diseases.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If anti-CD22 antibodies are used to treat hematopoietic cancers, then therapeutic efficacy is improved, but the mechanism of action is not well understood and toxicity may increase

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidunderstanding of mechanism of action

Core Design Contradiction:

ReliabilityVSLoss of information

Solution Approach 1:

The patent employs extensive CD22 cross-linking to trigger feedback signaling through BCR pathways, activating phosphorylation cascades (Lyn, ERKs, JNKs) that provide mechanistic feedback on how the antibody exerts its therapeutic effect, thereby improving understanding while maintaining efficacy

Inventive Principle:

Principle #23Feedback

2Productivity

If extensive CD22 cross-linking is induced, then apoptosis and BCR signaling are triggered improving cancer treatment, but direct cytotoxicity to normal B cells may increase

Engineering Contradiction:

Improveapoptosis induction in cancer cellsVSAvoiddirect cytotoxicity to normal B cells

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent utilizes parameter changes in the form of extensive CD22 cross-linking to shift the system from a state of inhibitory signaling to one of pro-apoptotic signaling, triggering phosphorylation of CD22, CD79a, and CD79b, and activating caspase-dependent apoptosis pathways that selectively affect malignant B cells while sparing normal B cells

Inventive Principle:

Principle #35Parameter changes

3Reliability

If CD22 is cross-linked to trigger apoptosis, then caspase-dependent pathways are activated, but the complexity of the signaling mechanism increases

Engineering Contradiction:

Improveapoptosis inductionVSAvoidsignaling mechanism complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent segments the complex apoptotic signaling mechanism into distinct, identifiable components: CD22 cross-linking triggers BCR signaling, which activates specific kinases (Lyn, ERKs, JNKs), leading to caspase activation and apoptosis. This segmentation allows each step to be studied and understood separately, reducing the perceived complexity while maintaining the full therapeutic effect

Inventive Principle:

Principle #1Segmentation

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

This approach effectively induces apoptosis in B cells and reduces BCR regulators on the surface, inhibiting B cell activation and providing therapeutic benefits for autoimmune and immune dysfunction diseases with reduced direct cytotoxicity to normal B cells.

Implementation Method 1

inducing phosphorylation of CD22, CD79a and CD79b

Methodology Applied

Scientific EffectPhosphorylation:

Implementation Method 2

leading to caspase-dependent apoptosis

Methodology Applied

Scientific EffectCaspase-dependent apoptosis:

Implementation Method 3

generation of reactive oxygen species (ROS)

Methodology Applied

Scientific EffectReactive oxygen species generation:

Implementation Method 4

trogocytosis of BCR-related antigens

Methodology Applied

Scientific EffectTrogocytosis:

Data Source

PatentUS9757458B2Crosslinking of CD22 by epratuzumab triggers BCR signaling and caspase-dependent apoptosis in hematopoietic cancer cells

Publication Date: 2017.09.12 IMMUNOMEDICS INC

AI summary

Extensive crosslinking of CD22 by plate-immobilized epratuzumab induced intracellular changes in Daudi cells similar to ligating B-cell antigen receptor (BCR) with a sufficiently high amount of anti-IgM. Either treatment leads to phosphorylation of CD22, CD79a and CD79b, along with their translocation to lipid rafts, both of which were needed to induce caspase-dependent apoptosis. Immobilization also induced stabilization of F-actin, phosphorylation of Lyn, ERKs and JNKs, generation of reactive oxygen species (ROS), decrease in mitochondria membrane potential (Δψm), upregulation of pro-apoptotic Bax, and downregulation of anti-apoptotic Bcl-xl and Mcl-1. Several of the in vitro effects of immobilized epratuzumab, including apoptosis, drop in Δψm, and generation of ROS, were observed with soluble epratuzumab in Daudi cells co-cultivated with human umbilical vein endothelial cells. The in vivo mechanism of non-ligand-blocking epratuzumab may, in part, involve the unmasking of CD22 to facilitate the trans-interaction of B cells with vascular endothelium.