Tetravalent TLR9-CD3 Bispecific Antibody for Enhanced Immunotherapeutic Tumor Targeting
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.
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.
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