Ag85B CAR-T Constructs for Bladder Tumor Infiltration

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Solution Overview

Problem

Current treatments for bladder cancer, such as intravesically instilled live-attenuated Bacillus Calmette-Guerin (BCG), have limited efficacy due to the heterogeneity of tumor cells, physical barriers for therapeutic T cells, and immunosuppressive regulatory T cells and myeloid-derived suppressor cells within the tumor microenvironment, making it difficult to achieve durable tumor regression.

Innovation Solution

Development of antibodies and chimeric antigen receptors (CARs) that specifically bind to BCG antigen Ag85B, combined with BCG, to enhance T cell recruitment and activation within the tumor microenvironment, overcoming barriers and immunosuppression.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If intravesically instilled live-attenuated BCG is used to treat bladder cancer, then tumor recurrence and progression are reduced, but treatment efficacy is limited due to tumor cell heterogeneity and physical barriers

Engineering Contradiction:

Improvetreatment efficacyVSAvoidtumor cell heterogeneity

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent generates polyclonal T cells that can recognize multiple tumor-associated antigens (TAAs) including Ag85B, creating a universal immune response that addresses tumor heterogeneity. The CAR T cell construct includes multiple antigen specificities, allowing a single therapy to target diverse tumor cell populations with different antigen expressions.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Solution Approach 2:

The invention combines BCG antigen Ag85B with other tumor-associated antigens in a composite CAR T cell construct. This composite approach integrates multiple antigen recognition capabilities into a single therapeutic product, enabling simultaneous targeting of heterogeneous tumor cell populations.

Inventive Principle:

Principle #40Composite materials

2Reliability

If high numbers of fully activated tumor-specific cytotoxic CD8+ T cells are used, then tumor regression may be induced, but T cell recruitment to tumor tissue is insufficient due to physical barriers

Engineering Contradiction:

Improvetumor regressionVSAvoidT cell recruitment speed

Core Design Contradiction:

ReliabilityVSSpeed

Solution Approach 1:

The patent uses BCG antigen Ag85B as an intermediary to enhance T cell recruitment. The antigen acts as a chemoattractant that guides T cells through the physical barriers of the tumor microenvironment to the tumor bed, improving infiltration speed and efficiency.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention modifies the chemical environment within the tumor microenvironment by introducing BCG antigen Ag85B, which changes the parameters of T cell migration. This creates favorable conditions for T cell infiltration by altering the chemical gradients and signaling pathways that regulate T cell movement through tissue barriers.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If immunosuppressive regulatory T cells and myeloid-derived suppressor cells are present in the tumor microenvironment, then T cell effector function is progressively lost, but removing these cells is complex

Engineering Contradiction:

ImproveT cell effector functionVSAvoidimmunosuppressive cell depletion

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent employs preliminary anti-action by using BCG antigen Ag85B to pre-activate and prime T cells before they encounter the immunosuppressive tumor microenvironment. This preliminary activation enhances T cell resilience and functionality, counteracting the suppressive effects of Tregs and MDSCs before they can inhibit effector function.

Inventive Principle:

Principle #9Preliminary anti-action

Solution Approach 2:

The invention converts the presence of immunosuppressive cells into a benefit by using BCG antigen Ag85B to stimulate robust T cell responses that can overcome suppression. The therapeutic approach transforms the challenging immunosuppressive environment into an opportunity for enhanced T cell activation and tumor-specific immunity.

Inventive Principle:

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

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

The approach enhances T cell infiltration and activation, demonstrating feasibility in bladder cancer treatment by increasing tumor-specific immune responses and potentially treating bladder cancer, lung cancer, and melanoma.

Implementation Method 1

an isolated antibody or antigen binding fragment thereof capable of binding Bacillus Calmette-Guerin (BCG) antigen Ag85B

Methodology Applied

Scientific EffectAntigen-antibody binding:

Data Source

PatentUS12522651B2BCG car constructs and methods of their manufacture and use

Publication Date: 2026.01.13 VERSITI BLOOD RESEARCH INSTITUTE FOUNDATION INC

AI summary

Provided herein are antibodies and antigen binding fragments thereof specific to BCG antigen Ag85B as well as chimeric antigen receptors and lymphocytes comprising Ag85B antibodies as described and methods of treating cancer and tuberculosis infections using the CAR lymphocytes described. In a first aspect, provided herein is an isolated antibody or antigen binding fragment thereof capable of binding Bacillus Calmette-Guerin (BCG) antigen Ag85B.