| 1. |
- Nelson, Michelle H., et al.
(författare)
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The Bispecific Tumor Antigen-Conditional 4-1BB x 5T4 Agonist, ALG.APV-527, Mediates Strong T-Cell Activation and Potent Antitumor Activity in Preclinical Studies
- 2023
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Ingår i: Molecular Cancer Therapeutics. - 1538-8514. ; 22:1, s. 89-101
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Tidskriftsartikel (refereegranskat)abstract
- 4-1BB (CD137) is an activation-induced costimulatory receptor that regulates immune responses of activated CD8 T and natural killer cells, by enhancing proliferation, survival, cytolytic activity, and IFNγ production. The ability to induce potent antitumor activity by stimulating 4-1BB on tumor-specific cytotoxic T cells makes 4-1BB an attractive target for designing novel immuno-oncology therapeutics. To minimize systemic immune toxicities and enhance activity at the tumor site, we have developed a novel bispecific antibody that stimulates 4-1BB function when co-engaged with the tumor-associated antigen 5T4. ALG.APV-527 was built on the basis of the ADAPTIR bispecific platform with optimized binding domains to 4-1BB and 5T4 originating from the ALLIGATOR-GOLD human single-chain variable fragment library. The epitope of ALG.APV-527 was determined to be located at domain 1 and 2 on 4-1BB using X-ray crystallography. As shown in reporter and primary cell assays in vitro, ALG.APV-527 triggers dose-dependent 4-1BB activity mediated only by 5T4 crosslinking. In vivo, ALG.APV-527 demonstrates robust antitumor responses, by inhibiting growth of established tumors expressing human 5T4 followed by a long-lasting memory immune response. ALG.APV-527 has an antibody-like half-life in cynomolgus macaques and was well tolerated at 50.5 mg/kg. ALG.APV-527 is uniquely designed for 5T4-conditional 4-1BB-mediated antitumor activity with potential to minimize systemic immune activation and hepatotoxicity while providing efficacious tumor-specific responses in a range of 5T4-expressing tumor indications as shown by robust activity in preclinical in vitro and in vivo models. On the basis of the combined preclinical dataset, ALG.APV-527 has potential as a promising anticancer therapeutic for the treatment of 5T4-expressing tumors.
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| 2. |
- Veitonmäki, Niina, et al.
(författare)
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A human icam-1 antibody isolated by a function-first approach has potent macrophage-dependent antimyeloma activity in vivo.
- 2013
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Ingår i: Cancer Cell. - : Elsevier BV. - 1878-3686 .- 1535-6108. ; 23:4, s. 502-515
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Tidskriftsartikel (refereegranskat)abstract
- We isolated a tumor B-cell-targeting antibody, BI-505, from a highly diversified human phage-antibody library, using a pioneering "function-first" approach involving screening for (1) specificity for a tumor B cell surface receptor, (2) induction of tumor programmed cell death, and (3) enhanced in vivo antitumor activity compared to currently used treatments. BI-505 bound to intercellular adhesion molecule-1, identifying a previously unrecognized role for this receptor as a therapeutic target in cancer. The BI-505 epitope was strongly expressed on the surface of multiple myeloma cells from both newly diagnosed and relapsed patients. BI-505 had potent macrophage-dependent antimyeloma activity and conferred enhanced survival compared to currently used treatments in advanced experimental models of multiple myeloma.
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| 3. |
- Veitonmäki, Niina
(författare)
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Angiostatic mechanisms of endogenous angiogenesis inhibitors
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Angiogenesis, the process of sprouting of new capillaries from the existing blood vessels, is essential for tumor growth and metastasis. Angiostatin was discovered as the first specific endogenous angiogenesis inhibitor nearly 10 years ago. The structure of angiostatin consists of the first three/four kringle (K1-3/K1-4) domains of plasminogen. However, plasminogen contains five kringle structures and it has been shown that kringle 5 (K5) displays at least as potent inhibitory activity as angiostatin in suppression of endothelial cell growth. This thesis work describes the discovery of kringle 1-5 (K1-5) as one of the most potent plasminogenderived angiogenesis inhibitors. It specifically inhibits endothelial cell growth in vitro and angiogenesis in vivo. In a mouse tumor model, K1-5 potently inhibits primary tumor growth at the dose of which angiostatin is inactive. Further mechanistic studies show that K1- 5 specifically induces endothelial apoptosis by binding to endothelial cell surface F0F1-ATP synthase, and activating caspases-3, -8, and -9. In vivo experiments show that endothelial apoptosis is essential for the angiostatic activity of K1-5. In addition to K1-5, we found that adiponectin, a secreted adipocytokine, potently inhibits angiogenesis and tumor growth. Similar to K1-5, adiponectin-induced endothelial apoptosis involves activation of procaspases. Thus, our findings demonstrate that induction of endothelial apoptosis is a common pathway for these endogenous inhibitors to specifically inhibit angiogenesis. In the effort of standardizing our in vitro assay systems, primary bovine capillary endothelial (BCE) cells were immortalized using human telomerase reverse transcriptase (hTERT), the catalytic subunit of telomerase nucleoriboprotein complex. Surprisingly we have found that the average telomere lengths in the hTERT-transfected cells are shorter than those found in primary pre-senescent cells, indicating that immortalization of these bovine endothelial cells must be mediated by alternative mechanisms. Our results indicate that one of the alternative mechanisms might include inactivation of p16 by hTERT-induced DNA methylation. This thesis work provides important information for developing therapeutic antiangiogenic agents in the treatment of angiogenesis- dependent diseases such as cancer and metastasis.
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