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Antibody Fusion Proteins with Disrupted Heparin- Binding Activity

技术应用: Although the initials studies are focused on one antibody-cytokine fusion protein containing IL-12 and targeting HER2/neu, there are a number of other therapeutic approaches involving targeted delivery of a broad spectrum of heparin-binding cytokines and chemokines that might also benefit from a reduction in non-specific tissue/heparin binding. It is possible that there could be major improvements in targeted anti-cancer immunotherapy in general that result from the proposed studies.

详细技术说明: Heparin sulfate is found throughout all tissues and commonly bound to the cell surface. Many signaling molecules such as growth factors, chemokines and cytokines bind to heparin present at the cell surface and in the extracellular matrix of all tissues. While this local heparin binding is an advantage when the cytokine is secreted in its normal environment to be locally retained, it may be a drawback when the cytokine is being delivered by a targeting device such as an antibody fusion protein. In a therapeutic antibody-cytokine fusion protein, the antibody provides the specificity to a tumor antigen and the fused cytokine provides an enhanced immune response to the tumor, thus concentrating the cytokine in the tumor microenvironment. However, the cytokine domain of the antibody fusion protein retains its ability to bind heparin, with the potential to bind non-specifically to a broad variety of cells and the extracellular matrix, thereby reducing its specificity, increasing the effective dose, and creating the potential for unfavorable side effects. To overcome this limitation, UCLA researchers have developed mutants of IL-12 that are able to stimulate the immune system while disrupting its heparin-binding domain.

*Abstract: Heparin sulfate is found throughout all tissues and commonly bound to the cell surface. Many signaling molecules such as growth factors, chemokines and cytokines bind to heparin present at the cell surface and in the extracellular matrix of all tissues. While this local heparin binding is an advantage when the cytokine is secreted in its normal environment to be locally retained, it may be a drawback when the cytokine is being delivered by a targeting device such as an antibody fusion protein. In a therapeutic antibody-cytokine fusion protein, the antibody provides the specificity to a tumor antigen and the fused cytokine provides an enhanced immune response to the tumor, thus concentrating the cytokine in the tumor microenvironment.
However, the cytokine domain of the antibody fusion protein retains its ability to bind heparin, with the potential to bind non-specifically to a broad variety of cells and the extracellular matrix, thereby reducing its specificity, increasing the effective dose, and creating the potential for unfavorable side effects. To overcome this limitation, UCLA researchers have developed mutants of IL-12 that are able to stimulate the immune system while disrupting its heparin-binding domain.

*Applications: Although the initials studies are focused on one antibody-cytokine fusion protein containing IL-12 and targeting HER2/neu, there are a number of other therapeutic approaches involving targeted delivery of a broad spectrum of heparin-binding cytokines and chemokines that might also benefit from a reduction in non-specific tissue/heparin binding. It is possible that there could be major improvements in targeted anti-cancer immunotherapy in general that result from the proposed studies.

*Principal Investigation: Name: Gustavo Helguera
Department:

Name: Rosendo Luria-Perez
Department:

Name: Manuel Penichet
Department:

附加资料: Patent Number: US20120321589A1
Application Number: US13581369A
Inventor: Penichet, Manuel L. | Luria-Perez, Rosendo | Helguera, Gustavo
Priority Date: 12 Mar 2010
Priority Number: US20120321589A1
Application Date: 27 Aug 2012
Publication Date: 20 Dec 2012
IPC Current: C07K001900 | A61K0039395 | C12N000507 | C12N000510 | C12N001562 | C12N001585
US Class: 4240851 | 4353201 | 435328 | 435375 | 530351 | 5303873 | 5360234
Title: Antibody Fusion Proteins with Disrupted Heparin-Binding Activity
Usefulness: Antibody Fusion Proteins with Disrupted Heparin-Binding Activity
Summary: For treating a subject having cancer, for inducing cell proliferation in a cell; and for reducing the non-specific binding and/or the non-specific localization of an antibody fused to a cytokine (claimed).
Novelty: New polypeptide for treating cancer comprises antibody linked to cytokine which has a modified heparin binding region which disrupts, inhibits, or reduces the ability of the cytokine to bind a heparin compound

其他

Additional Technologies by these Inventors

Tech ID/UC Case

21182/2010-594-0

Related Cases

2010-594-0

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