Siglec Chimeric Receptors That Turn Tumor Binding Into Immune Activation

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Solution Overview

Problem

Cancer cells evade immune response by expressing sialic acids that interact with ITIM-containing Siglec receptors, inhibiting NK cell activation, necessitating a targeted approach to counter this mechanism.

Innovation Solution

Development of chimeric receptors comprising an extracellular domain of Siglec-7 or Siglec-9 capable of binding their ligands, with intracellular domains that transmit activating or co-stimulatory signals to immune cells, such as CD3 zeta or CD28, to enhance immune cell activation against cancer cells.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Measurement precision

If Siglec receptors with ITIM domains are used to target cancer cells, then cancer cell recognition is improved, but immune cell activation is inhibited

Engineering Contradiction:

Improvecancer cell recognitionVSAvoidimmune cell activation

Core Design Contradiction:

Measurement precisionVSReliability

Solution Approach 1:

The patent inverts the natural function of Siglec receptors by replacing their inhibitory intracellular domains (containing ITIMs) with activating domains (containing ITAMs or other activating motifs). This creates chimeric receptors that maintain the ability to recognize cancer cells via sialic acid binding in the extracellular domain, while the intracellular domain now transmits activating signals to promote immune cell function rather than inhibition.

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The patent creates composite receptor structures by combining the extracellular ligand-binding domain of Siglec receptors with intracellular signaling domains from other receptors (such as CD3 zeta, FcR gamma, or other activating domains). This composite structure integrates the cancer-specific recognition capability of Siglecs with the activating signaling capability of other immune receptors, resolving the contradiction between recognition and activation.

Inventive Principle:

Principle #40Composite materials

2Reliability

If sialic acids are expressed on cancer cells to evade immune response, then immune evasion is improved, but immune cell activation is reduced

Engineering Contradiction:

Improveimmune evasionVSAvoidimmune cell activation

Core Design Contradiction:

ReliabilityVSPower

Solution Approach 1:

The patent converts the harmful effect of sialic acid expression on cancer cells (which normally leads to immune suppression via Siglec binding) into a beneficial effect. By engineering chimeric receptors that use sialic acid binding as the trigger for activation rather than inhibition, the presence of sialic acids on cancer cells now serves as a positive signal for immune cell activation and tumor cell killing, transforming the cancer cell's escape mechanism into its vulnerability.

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Data Source

PatentUS12570714B2Siglec-based chimeric polypeptides and uses thereof

Publication Date: 2026.03.10 BAR ILAN UNIV

AI summary

Provided are Siglec-based chimeric polypeptides. Accordingly there is provided a chimeric receptor comprising: (a) an extracellular domain comprising an amino acid sequence of a Siglec-7 or a Siglec-9 receptor capable of binding a Siglec-7 and/or a Siglec-9 ligand; and (b) an intracellular domain comprising an amino acid sequence capable of transmitting a co-stimulatory signal in an immune cell expressing the chimeric receptor upon binding of said extracellular domain to said ligand. Also provided are polynucleotides encoding same, cells expressing same and methods of use thereof.