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Tetravalent TLR9-CD3 Bispecific Antibody for Enhanced Immunotherapeutic Tumor Targeting

Technology Application

TLR9 is normally expressed in lysosomes where it functions in the innate response to infection. In many tumor types including melanoma, breast, esophagus, colon/rectum, lung, ovary, cervix endometrium and cancers of the blood, TLR9 is aberrantly expressed in the plasma membrane, indicating a large potential market (over 777,00 patients) who could benefit from a tumor-selective, TLR9 targeted therapy. Many treatments for blood malignancies such as MDS and AML are accompanied by significant systemic toxicities. For example, nucleoside analogies are standard, however, they can be associated with side effects such as nausea, cytopenias, pain, liver and kidney toxicity and increased risk of infections. Harnessing a patientΓÇÖs own immune system to recognize & kill cancer cells has been a desirable strategy for years. Chimeric antigen receptor T-cell (CAR-T) immunotherapy is an elegant method of genetically engineering autologous T-cells to recognize the patientΓÇÖs tumor and destroy it, however, the method is technically challenging, time consuming and labor intensive. The first CAR-T based immunotherapy (CTL019; Novartis) received breakthrough drug designation from the US FDA for relapsed/refractory ALL and B-cell malignancies in July 2014. Bi-specific T-cell engagers (BiTEs) are chimeric bi-specific monoclonal antibodies that recognize T-cells & direct them to antigens such as CD19 on B-cell malignancies (e.g., blinatumomab or AMG-103) to selectively kill tumor cells. Although highly clinically active, because of their small molecular size permitting renal filtration, they must be administered by prolonged continuous infusions with significant systemic toxicity. This novel tetrameric bispecific antibody could become a best-in-class targeted immunotherapy that seeks results similar to CAR-T or BiTE therapy with greater convenience of administration.

Detailed Technology Description

The bispecific anti-CD3-TLR9 contains two binding sites for each receptor (tetravalent) and engages T-cells to destroy TLR9 expressing malignant cells. In MDS patient samples from Moffitt, bone marrow mononuclear cells were shown to overexpress membrane TLR9 vs. normal bone marrow cells (p<0.00005), with particular up-regulation in malignant stem cells. Tetravalent bispecific molecules have more favorable safety and PK profiles given their larger size and permit rapid infusion with greater T-cell engagement.

*Abstract

A synergistic increase in apoptosis occurs when myeloproliferative neoplasm primary cells are treated simultaneously with inhibitors of BRD4 and JAK2, and when AML cell lines are treated with inhibitors of BRD4 and FLT3. Moreover, in vitro studies suggest that JAK1/JAK2 inhibitor resistant cells remain sensitive to BRD4 inhibitor-induced apoptosis suggesting our dual inhibitor may be useful in JAK1/JAK2 sensitive or resistant cancers. The market for BRD4 inhibitors is attractive as evidenced by five companies developing small molecules that inhibit BRD2-4 and BRD3-4 for hematologic malignancies, NUT midline carcinoma, and advanced solid cancers. At least one inhibitor, OncoEthixΓÇÖs OTX015, has progressed to Phase II, suggesting that inhibition of BRD4 is not deleterious.Our dual BRD4/JAK2 inhibitors have IC50s for JAK2 that are comparable to those of the JAK2 inhibitors currently in the clinic and on the market. Ruxolotinib, IncyteΓÇÖs and NovartisΓÇÖ JAK1/JAK2 inhibitor, has already been approved for myelofibrosis, a rare bone cancer, as well as psoriasis, and rheumatoid arthritis. Several other JAK2 inhibitors are in Phase II & III clinical trials, alone and in combination, for a number of solid tumors and hematologic malignancies.

Country/Region

USA