We are passionate about delivering lasso-based cures to patients suffering from debilitating diseases. Our current pipeline of lasso therapeutics offers a new approach to treating challenging cancers.
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ETBR (Endothelin B Receptor) is a GPCR that is overexpressed on tumor vasculature endothelia and reduces production of ICAM-1, which is required for immune cell infiltration into tumors. ETBR expression leads to immunologically “cold” tumors that have attenuated anti-tumor immune responses and resistance to immunotherapy. Lassotides that block ETBR are being developed to treat challenging cancers that respond poorly to existing immuno-oncology agents.
Lasso peptides have been found to bind to ETBR and Lassogen is employing its platform and DBTE workflow to design and engineer novel analogs that are potent and selective antagonists of this receptor.
Our lead lassotide displays excellent stability, safety (no immunogenicity or off-target activity), pharmacokinetic properties (in vivo t½ = 7 h in mice), and tissue distribution. In vivo dosing was shown to sharply increase immune cell infiltration into the tumor microenvironment and significantly enhance checkpoint inhibitor efficacy when used as a combination therapy in syngeneic mouse tumor models that overexpress ETBR.
Buckanovich et al. Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy (2008). Nature Medicine, 14(1), 28-36. (PubMed)
Kandalaft et al. Endothelin B Receptor, a New Target in Cancer Immune Therapy (2009). Clin Cancer Res.,15(14), 4521–4528. (PubMed)
Coffman et al., Endothelin receptor-A is required for the recruitment of anti-tumor T cells and modulates chemotherapy induction of cancer stem cells (2013). Cancer Biology & Therapy, 14(2), 184–192. (PubMed)
Karaki et. al. RES-701-1: A novel endothelin ETB receptor antagonist (1996). Cardiovascular Drug Reviews, 14(1), 17-35. (View PDF)
Integrin αvβ6 is a cell surface adhesion receptor that is overexpressed on a broad range of cancers and facilitates tumor invasion and metastasis. In addition, αvβ6 is one of the main activators of latent transforming growth factor beta (TGFβ), which leads to an immunosuppressed tumor microenvironment (TME). Agents that selectively inhibit αvβ6-driven cell adhesion and TGFβ activation are being developed to treat malignancies that proliferate and spread by exploiting this receptor.
Lassotides are being computationally designed and engineered to specifically target the αvβ6 receptor. The known RGD binding epitope has been introduced into a range of lasso scaffolds with different structures and the surrounding amino acids are being varied to afford an optimized binding interface with the receptor. SAR studies are revealing the rules for achieving both high potency and high αvβ6 selectivity with engineered lassotides.
Designed lassotides have been discovered that are potent and selective inhibitors of αvβ6. These novel leads are being explored to demonstrate efficacy in blocking αvβ6-driven metastasis and activation of TGFβ in the TME. Drug conjugates and combinations with various immunotherapies are being investigated as treatments for a variety of difficult cancers such as ovarian, pancreatic, breast, and lung carcinomas that overexpress αvβ6.
Niu et al. The roles of integrin αvβ6 in cancer (2017). Cancer Letters, 403, 128e137 (PubMed)
Koivisto et al. Integrin αvβ6: structure, function and role in health and disease (2018). Int.J. Biochem. Cell Biol. 99,186-196. (PubMed)
Meecham et al. The ITGFβ gene: its role in experimental and clinical biology (2020). Gene: X, 5, 100023. (PubMed)
Eberlein et al., A human monoclonal antibody 264RAD targeting αvβ6 integrin reduces tumour growth and metastasis and modulates key biomarkers in vivo (2013). Oncogene, 32, 4406–4416. (PubMed)
Bagati et al. Integrin αvβ6–TGFβ–SOX4 pathway drives immune evasion in triple-negative breast cancer (2021). Cancer Cell, 39, 54–67. (PubMed)
Soejima et al. ITGB6-knockout suppresses cholangiocarcinoma cell migration and invasion with declining PODXL2 expression (2021). Int. J. Mol. Sci., 22, 6303. (PubMed)
Integrin αvβ8 is an adhesion receptor that is overexpressed on a broad range of tumor and immune cells and promotes immunosuppression in the tumor microenvironment by activating latent TGFβ. Selective inhibitors of αvβ8-driven TGFβ activation are being developed to enhance the anti-tumor immune response against a range of cancers.
Lassotides are being computationally designed and engineered to specifically target the αvβ8 receptor. The known RGD binding epitope has been grafted into a range of lasso scaffolds and the surrounding ring and loop amino acids are being varied to yield an optimized binding interface with the receptor. SAR studies are revealing the rules for achieving both high potency and high αvβ8 selectivity with our engineered lassotides.
Potent and selective inhibitors of αvβ6 and αvβ8 have been designed. These novel leads are being explored in vitro and in vivo for inhibition of TGFβ activation in the TME and efficacy in cancer models. Combinations of αvβ8-targeted lassotides with various immunotherapies are being investigated as treatments for a variety of difficult malignancies such as colon, breast, metastatic melanoma, and squamous cell tumors that overexpress αvβ8.
Worthington et al. Integrin αvβ8-Mediated TGF-β Activation by Effector Regulatory T Cells Is Essential for Suppression of T-Cell-Mediated Inflammation (2015). Immunity, 42,903–915. (PubMed)
Stockis et al. Blocking immunosuppression by human Tregs in vivo with antibodies targeting integrin αVβ8 (2017). Proc Natl Acad Sci USA, 114(47): E10161-E10168. (PubMed)
Takasaka et al. Integrin αvβ8–expressing tumor cells evade host immunity by regulating TGF-β activation in immune cells (2018). JCI Insight, 3(20): e122591. (PubMed)
Dodagatta-Marri et al. Integrin αvβ8 on T cells suppresses anti-tumor immunity in multiple models and is a promising target for tumor immunotherapy (2021). Cell Reports, 36, 109309. (PubMed)
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