Application of GARP antibodies and fusion proteins in cancer, inflammatory and immune conditions

Description:

Technology: Researchers at MUSC have demonstrated GARP is a novel oncogene due to its cancer-intrinsic roles in promoting invasion and metastasis, as well as its cancer-extrinsic roles in inducing immune tolerance. Multiple antibodies have been produced, one of which (4D3) specifically blocks the association between GARP and TGFβ, greatly reducing active TGFβ (data not shown). Administration of 4D3 limited metastasis, reduced Tregs in the tumor microenvironment and resulted in an effective cancer therapy in a mouse model of breast cancer when combined with Cy (Fig 1). 

 

To test the role of the GARP-TGFβ axis in Adoptive Cell Therapy (ACT), mice with a selective deletion of GARP in platelets (Plt-GARPKO) were generated. GARPKO mice had a better response to ACT in melanoma (data not shown) and colon cancers (Fig. 2). Plt-GARPKO mice also displayed a remarkable reduction of active TGFβ, myeloid-derived suppressor cells and tumor infiltrating Tregs. Further work found anti-platelet agents such as aspirin potentiate the effects of ACT. Taken together, this work demonstrates platelet GARP is a commanding source of TGFβ activity in the tumor microenvironment and that GARP exerts potent immunosuppressive effects on antitumor immunity via the GARP-TGFβ axis.

This research uncovers a novel therapeutic antibody 4D3 that blocks the association between TGFβ and GARP, which as a result reduces active TGFβ. 4D3 exerts in vivo effects as an anticancer agent alone and in combination with other chemotherapeutics, and shows promise with for ACT therapies. Also, this work suggests anti-platelet drugs may be used as anti-cancer agents in combination with other chemotherapeutics and/or ACT therapies.

 

Overview: GARP expression is found on the cell surface of regulatory T cells, platelets and other activated leukocytes. GARP is aberrantly expressed in colon, lung, myeloma and prostate cancers. In addition, higher levels of GARP correlate with worse patient prognosis. GARP is believed to be a key regulator in maintaining cell surface TGFβ expression and downstream signaling, which controls a diverse set of oncogenic processes and is a master regulator at allowing cancer to evade tumor immunity. GARP expression appears to be a biomarker for cancer diagnosis and prognosis, and targeting GARP with specific antibodies could be a novel therapeutic platform for cancer by blocking TGFβ availability. In addition, GARP-based antibodies might also be applicable for depleting regulatory T cells and platelets in vivo for boosting immune response and ablating platelet disorders respectively. There are currently no treatment modalities for cancer or autoimmune diseases based on anti-GARP antibodies.

Applications: Treatment and detection of cancers, including colon, lung, myeloma, and prostate cancers as a single or combination therapy. Modulating GARP for treatment of inflammatory and immune disorders.

Advantages:  Reduced metastasis, biomarker for cancer, treatment for cancers, combination immunotherapy, treatment for inflammatory and immune conditions

Key Words: GARP, protein, monoclonal antibody, cancer, inflammatory disease, autoimmune, TGFβ, immunotherapy, tumor, biomarker,  

Publications: Metelli, Alessandra, et al. "Surface Expression of TGFβ Docking Receptor GARP Promotes Oncogenesis and Immune Tolerance in Breast Cancer." Cancer Research 76.24 (2016): 7106-7117.

 

Rachidi, et al. “Platelets subvert T cell immunity against cancer via GARP-TGFβ axis.” Science Immunology 2.11 (2017).

 

Inventors: Zihai Li

Patent Status: PCT/US2017/173091

MUSC-FRD Technology ID: P1426 and P1428

 

Patent Information:
Category(s):
Therapeutic
For Information, Contact:
Scott Davis
Sr Licensing Manager
MUSC Foundation for Research Development
843-876-1900
davissco@musc.edu
Inventors:
Zihai Li
Keywords:
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