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Advanced Control in Cellular Therapies with Molecular Switch Technology

Introduction

Cellular therapies hold immense promise for treating a wide array of diseases, from cancer to autoimmune disorders. However, one of the biggest challenges with cellular therapies is the ability to precisely control therapeutic activity, ensuring it targets only diseased cells without affecting healthy tissues. Our patented Antibody Chemically Induced Dimerizer (AbCID) technology offers a novel solution for regulating cellular therapies with unprecedented precision. This technology enables researchers and healthcare providers to activate or deactivate specific cellular therapies on demand, improving safety, efficacy, and flexibility.

Limitations of Current Cellular Therapies

While cellular therapies, such as CAR-T cells, have shown remarkable success in treating certain cancers, the challenge remains in controlling these therapies once they are introduced into the body. Current methods often lack the precision needed to prevent unintended side effects, such as immune overactivation or off-target damage to healthy cells. Without the ability to regulate these therapies in real-time, patients face the risk of severe adverse reactions, which can compromise treatment success.

There is a growing need for a technology that allows healthcare providers to fine-tune cellular therapies, ensuring that they remain effective while minimizing potential harm to the patient.

A New Approach to Cellular Therapy Control

Our AbCID technology offers an innovative molecular switch that can control cellular therapies with chemical precision. By introducing a dimerizer system that is activated by specific antibodies, this technology allows for the real-time regulation of therapeutic activity at the molecular level. The dimerizer can activate or deactivate cellular functions, making it possible to switch the therapy on or off based on the patient’s response. This provides an added layer of safety, ensuring that therapies are only active when needed and reducing the risk of unintended side effects.

This system is highly adaptable and can be integrated into a wide range of cellular therapies, including cancer treatments, gene therapies, and immune-modulating therapies. By offering precision control over therapeutic action, AbCID enables more personalized and responsive treatments for patients, improving both efficacy and safety.

Key Benefits

  • Precision Control: Allows for on-demand activation and deactivation of cellular therapies, ensuring precise targeting of diseased cells.
  • Enhanced Safety: Reduces the risk of adverse side effects by providing real-time regulation of therapeutic activity.
  • Broad Applicability: Can be applied to a variety of cellular therapies, including cancer, autoimmune, and genetic treatments.
  • Improved Patient Outcomes: Enables more tailored, responsive therapies that can be adjusted based on patient needs.

Transforming the Future of Cellular Therapies

Licensing this molecular switch technology offers pharmaceutical companies and biotechnology firms a cutting-edge tool for advancing cellular therapies. With its ability to provide precision control over therapeutic activity, this technology opens new doors for safer, more effective treatments in oncology, immunotherapy, and beyond.

Please see terms and conditions
Chemically induced dimerizers (AbCIDs) have emerged as one of the most powerful tools to artificially regulate signaling pathways in cells; however, no facile method to identify or design these systems currently exists. The present invention provides a methodology to rapidly generate antibody-based chemically induced dimerizers (AbCIDs) from known small-molecule-protein complexes by selecting for synthetic antibodies that recognize the chemical epitope created by the bound small molecule. Success of this strategy is demonstrated by generating ten chemically-inducible antibodies against the BCL-xL/ABT-737 complex. Three of the antibodies are highly selective for the BCL-xL/ABT-737 complex over BCL-xL alone. Two exemplary important cellular applications of AbCIDs are demonstrated by applying them intracellularly to induce CRISPRa-mediated gene expression and extracellularly to regulate CAR T-cell activation with the small molecule, ABT-737. ABT-737 is not toxic at the concentrations used to activate AbCIDs in cells. AbCIDs provided by this invention are new and orthogonal AbCIDs, expanding the limited toolbox of available CIDs.

What is claimed is:

1. A system comprising:

(a) a first chemically-induced dimer (CID) component comprising (i) a first binding moiety that is a protein capable of interacting with a small molecule to form a complex; and (ii) a first adapter moiety linked to the first binding moiety; and
(b) a second CID component comprising (i) a second binding moiety that is a protein that binds to the complex between the small molecule and the first binding moiety at a site of the complex comprising at least a portion of the small molecule and a portion of the first binding moiety; and (ii) a second adapter moiety linked to the second binding moiety;
wherein the binding of the second binding moiety to the complex between the small molecule and the first binding moiety creates a dimer between the second CID component and the first CID component,
wherein the first adapter moiety comprises a T cell antigen-binding moiety and the second adapter moiety comprises a target cell antigen-binding moiety; or the second adapter moiety comprises a T cell antigen-binding moiety and the first adapter moiety comprises a target cell antigen-binding moiety,
wherein the target cell antigen-binding moiety is an extracellular antigen-binding moiety,
wherein the first CID component comprises an ABT-199 binding domain comprising the amino acid sequence of SEQ ID NO:315; and
wherein the second CID component comprises an antibody moiety comprising three heavy chain complementarity determining regions (CDRs) and three light chain CDRs of an antibody clone selected from antibody clone FAB-AZ11, FAB-AZ12, FAB-AZ13, FAB-AZ14, FAB-AZ15, FAB-AZ16, FAB-AZ17, FAB-AZ18, FAB-AZ19, FAB-AZ20, FAB-AZ21, FAB-AZ22, FAB-AZ23, FAB-AZ24, FAB-AZ25, FAB-AZ26, FAB-AZ27, FAB-AZ28, FAB-AZ29, FAB-AZ30, FAB-AZ31, FAB-AZ32, FAB-AZ33, FAB-AZ34, FAB-AZ35, FAB-AZ36, FAB-AZ37, FAB-AZ38, FAB-AZ39, FAB-AZ40, FAB-AZ41, FAB-AZ42, and FAB-AZ43.
2. The system of claim 1, wherein the second binding moiety binds to the complex between the small molecule and the first binding moiety with a dissociation constant (Kd) no more than 1/250 its Kd for each of an unbound form of the small molecule and an unbound form of the first binding moiety.
3. The system of claim 1, wherein the first binding moiety is a naturally occurring binding partner of the small molecule.
4. The system of claim 1, wherein when the second CID component and the first CID component are dimerized in the presence of the small molecule, the dimer formed is capable of binding a T cell and a target cell and redirecting the T cell to the target cell.
5. The system of claim 4, wherein the dimer formed is capable of modulating an immune response to the target cell.
6. The system of claim 4, wherein the T cell antigen is CD3.
7. The system of claim 1, wherein the first adapter moiety comprises the T cell antigen-binding moiety, and the second adapter moiety comprises the target cell antigen-binding moiety.
8. The system of claim 1, wherein the second adapter moiety comprises the T cell antigen-binding moiety, and the first adapter moiety comprises the target cell antigen-binding moiety.
9. The system of claim 1, wherein the second binding moiety is an antibody moiety.

10. A system comprising:

(a) a first chemically-induced dimer (CID) component comprising (i) a first binding moiety that is a protein capable of interacting with a small molecule to form a complex; and (ii) a first adapter moiety linked to the first binding moiety; and
(b) a second CID component comprising (i) a second binding moiety that is an antibody moiety that binds to the complex between the small molecule and the first binding moiety at a site of the complex comprising at least a portion of the small molecule and a portion of the first binding moiety; and (ii) a second adapter moiety linked to the second binding moiety;
wherein the binding of the second binding moiety to the complex between the small molecule and the first binding moiety creates a dimer between the second CID component and the first CID component,
wherein the first adapter moiety comprises a T cell antigen-binding moiety and the second adapter moiety comprises a target cell antigen-binding moiety; or the second adapter moiety comprises a T cell antigen-binding moiety and the first adapter moiety comprises a target cell antigen-binding moiety,
wherein the target cell antigen-binding moiety binds to a target antigen expressed on the surface of a target cell wherein the first CID component comprises an ABT-199 binding domain comprising the amino acid sequence of SEQ ID NO:315; and
wherein the second CID component comprises an antibody moiety comprising three heavy chain complementarity determining regions (CDRs) and three light chain CDRs of an antibody clone selected from antibody clone FAB-AZ11, FAB-AZ12, FAB-AZ13, FAB-AZ14, FAB-AZ15, FAB-AZ16, FAB-AZ17, FAB-AZ18, FAB-AZ19, FAB-AZ20, FAB-AZ21, FAB-AZ22, FAB-AZ23, FAB-AZ24, FAB-AZ25, FAB-AZ26, FAB-AZ27, FAB-AZ28, FAB-AZ29, FAB-AZ30, FAB-AZ31, FAB-AZ32, FAB-AZ33, FAB-AZ34, FAB-AZ35, FAB-AZ36, FAB-AZ37, FAB-AZ38, FAB-AZ39, FAB-AZ40, FAB-AZ41, FAB-AZ42, and FAB-AZ43.

11. A system comprising:

(a) a first chemically-induced dimer (CID) component comprising (i) a first binding moiety that is a protein capable of interacting with a small molecule to form a complex; and (ii) a first adapter moiety linked to the first binding moiety; and
(b) a second CID component comprising (i) a second binding moiety that is an antibody moiety that binds to the complex between the small molecule and the first binding moiety at a site of the complex comprising at least a portion of the small molecule and a portion of the first binding moiety; and (ii) a second adapter moiety linked to the second binding moiety;
wherein the binding of the second binding moiety to the complex between the small molecule and the first binding moiety creates a dimer between the second CID component and the first CID component,
wherein the first adapter moiety comprises a T cell antigen-binding moiety and the second adapter moiety comprises a target cell antigen-binding moiety; or the second adapter moiety comprises a T cell antigen-binding moiety and the first adapter moiety comprises a target cell antigen-binding moiety,
wherein the first CID component comprises an ABT-199 binding domain comprising the amino acid sequence of SEQ ID NO:315; and
wherein the second CID component comprises an antibody moiety comprising three heavy chain complementarity determining regions (CDRs) and three light chain CDRs of an antibody clone selected from antibody clone FAB-AZ11, FAB-AZ 12, FAB-AZ 13, FAB-AZ 14, FAB-AZ 15, FAB-AZ 16, FAB-AZ17, FAB-AZ18, FAB-AZ19, FAB-AZ20, FAB-AZ21, FAB-AZ22, FAB-AZ23, FAB-AZ24, FAB-AZ25, FAB-AZ26, FAB-AZ27, FAB-AZ28, FAB-AZ29, FAB-AZ30, FAB-AZ31, FAB-AZ32, FAB-AZ33, FAB-AZ34, FAB-AZ35, FAB-AZ36, FAB-AZ37, FAB-AZ38, FAB-AZ39, FAB-AZ40, FAB-AZ41, FAB-AZ42, and FAB-AZ43.
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Title

Antibody chemically induced dimerizer (AbCID) as molecular switches for regulating cellular therapies

Inventor(s)

James A Wells, Zachary B. HILL, Alexander J. MARTINKO

Assignee(s)

University of California, Antheia Inc

Patent #

11939379

Patent Date

March 26, 2024

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