Cirmtuzumab is a first-in-class humanized monoclonal antibody that binds with high affinity to a biologically important epitope on ROR1 (Receptor-tyrosine kinase-like Orphan Receptor 1). ROR1 is a type 1 transmembrane protein, essential for fetal development, that is expressed on the plasma membrane with an extracellular domain that is essential for ligand binding and signal transduction.

Cirmtuzumab binds to many different types of cancer but does not recognize normal adult tissues. When expressed by hematologic malignancies, such as mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), ROR1 acts as a receptor for the tumor growth factor Wnt5a. Cirmtuzumab binds to ROR1 and blocks Wnt5a-mediated ROR1 activation, induces differentiation of the tumor cells, and inhibits tumor cell proliferation, migration and survival. Preclinical models and early clinical data indicate that Cirmtuzumab synergizes with ibrutinib (marketed as IMBRUVICA®) as a potential combination treatment for CLL and MCL.

Cirmtuzumab is currently in a Phase 1/2 clinical trial in combination with ibrutinib as a treatment for chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) [NCT03088878]. A separate investigator-initiated Phase 1 study of cirmtuzumab in combination with paclitaxel for women with unresectable or metastatic Her2-negative breast cancer is also enrolling patients at UC San Diego [NCT02776917].

TK216 is a first-in-class small molecule inhibiting the biological activity of ETS-family transcription factor oncoproteins in a variety of tumor types. The ETS (E26 Transformation-Specific) transcription factor family (including family members FLI1, ERG, ETV1, ETV4, ETV5, ETV6, ETS1, ETS2, and SPIB) has been implicated as oncogenes, or genes that have been identified as important for the development or progression of cancer. While they are important in embryogenesis, these ETS-family proteins are not commonly expressed after birth, presenting a target for researchers hoping to selectively affect cancer cell growth.

In Ewing sarcoma, the cancer is caused by a single and well-characterized gene translocation that leads to a chimeric ETS protein, usually EWS-FLI1, which is readily detected with DNA or RNA-based testing. The ETS-family proteins are also over-expressed in various other cancers, including acute myeloid leukemia, aggressive lymphoma, and prostate cancer.

TK216 is currently being evaluated alone and in combination with vincristine in a Phase 1 study in patients with relapsed or refractory Ewing sarcoma, a pediatric bone and soft tissue cancer [NCT02776917].

Oncternal is developing a ROR1 targeting Chimeric antigen receptor T (CAR-T) cell therapy, which is currently in preclinical development in collaboration with UC San Diego for hematologic and solid tumors, with funding from the California Institute for Regenerative Medicine (CIRM).

CAR-T cell therapies utilize engineered T cells to target and engage a specific marker on cancer cells in an effort to direct an immune response against those cancer cells. ROR1 is highly expressed on many solid and hematologic cancers, but the ROR1 targeting portion of the CAR-T does not recognize healthy adult tissue.

Importantly, ROR1 expression confers a survival advantage to the tumor cells, making ROR1 negative relapses less likely. Oncternal’s ROR1 CAR-T specifically lysed ROR1+ target cells and inhibited ROR1+ tumors in vivo.

Oncolytic viruses hold promise as a new therapeutic strategy for the treatment of cancer. The first commercialized oncolytic virus product in the world, Oncorine (H101), developed by Shanghai Sunway Biotech Co., Ltd (a business unit of SPH), was approved by the Chinese SFDA in November, 2005 for nasopharyngeal carcinoma in combination with chemotherapy. cGMP manufacturing and market launch occurred in 2006.

SPHBio will evaluate the potential for development of Oncorine or oncolytic viruses based on the Oncorine construct in the U.S.

Antibody-drug conjugates or ADCs are a new class of highly potent biopharmaceutical drugs composed of an antibody linked, via a chemical linker, to a biologically active drug or cytotoxic compound. These novel, targeted agents combine the unique and very sensitive targeting capabilities of antibodies allowing sensitive discrimination between healthy and cancer cells with the cell-killing ability of cytotoxic drugs.

SPH is developing several novel ADCs for the treatment of HER2-positive metastatic breast cancer and for Hodgkin lymphoma and anaplastic large cell lymphoma. SPHBio will evaluate launching clinical development of these ADCs in the U.S.