作者: Wang, Shuhua ; Zhang, Hanwen ; Wang, Wenxi ; Zeng, Fanyuan ; Yang, Hua ; Chen, Zihan ; Li, Ying ; Giver, Cynthia R ; Li, Yiwen ; Grossniklaus, Hans E ; Waller, Edmund K ; Mendoza, Pia R ; Hsu, Po-Chih ; Jankowski, Shayna E ; Lesinski, Gregory B ; Li, Jian-Ming ; Passang, Tenzin

Uveal melanoma (UVM) is resistant to immune checkpoint therapy and chemotherapy, resulting in high mortality rates, primarily due to liver metastases. While vasoactive intestinal peptide (VIP) signaling has been identified as an immune checkpoint and therapeutic target in pancreatic cancer, its role in melanoma remains unexplored. This study investigated the impact of a novel VIP receptor antagonist, ANT308, on melanoma cell behavior and tumor growth. Using both murine and human UVM/cutaneous melanoma cell lines, we examined the inhibition of VIP receptor signaling and its effects on cell migration and proliferation in vitro. Mechanistically, ANT308 downregulated melanoma cell adhesion molecule (MCAM) and N-cadherin expression at both the RNA and protein levels, as demonstrated by RNA sequencing and Western blot analyses. Knockdown of the VIP receptor VPAC2 in mouse and human melanoma cells produced similar effects on cell migration, proliferation, and MCAM protein expression, further implicating VIP-VPAC2 signaling in tumor progression. In vivo studies revealed that ANT308 treatment decreased MCAM expression in intraocular primary tumors, reduced the number and size of liver metastases following intraocular or subcutaneous melanoma injection, and showed a trend toward reduced tumor volume at the primary tumor site. In conclusion, our findings indicate that VIP receptor signaling promotes liver metastasis in melanoma, and targeting this pathway with VIP receptor antagonists may represent a novel therapeutic strategy for treating metastatic UVM.

Identification and characterization of vasoactive intestinal peptide receptor antagonists with high-affinity and potent anti-leukemia activity

Article

作者: Papadantonakis, Nikolaos ; Wang, Shuhua ; Bruk, Nabute ; Giver, Cynthia ; Chaudagar, Kiranj ; Li, Yiwen ; Wang, Yuou ; Sen-Majumdar, Anish ; Giver, Cynthia R. ; Das, Pankoj Kumar ; Li, Jian-Ming ; Waller, Edmund K. ; Sarkar, Srijon ; Cohen, Jamie ; Chen, Zihan ; Passang, Tenzin ; Waller, Edmund K

ABSTRACT:

Vasoactive intestinal peptide (VIP) is a neuropeptide involved in tumor growth and immune modulating functions. Previous research indicated that a VIP antagonist (VIPhyb) enhances T-cell activation and induces T-cell-dependent anti-leukemic activity in mice. We created a combinatorial library of VIPhyb C-terminal sequence variations to develop a more potent VIP-receptor (VIP-R) antagonist, hypothesizing that specific amino acid substitutions would improve receptor binding and plasma stability.In silicoscreening analyses identified sequences with improved docking scores predicting increased binding affinity to human VIP receptors VPAC1 and VPAC2. Fifteen peptides were synthesized and tested for their ability to potentiate activation of purified mouse and human T cells and enhance T cell-dependent anti-leukemia responses in murine models of acute myeloid leukemia. Treating C57Bl/6 mice engrafted with a C1498 myeloid leukemia cell line with daily subcutaneous injections of VIP-R antagonist peptides induced T cell activation resulting in specific anti-leukemia responses. Strikingly, the predicted binding affinity of the VIP-R antagonists to VIP receptors correlated positively with their ability to augment mouse T-cell proliferation and anti-leukemia activity. ANT308 and ANT195 emerged as top candidates due to their high predicted VIP-R binding, low EC50forin vitroT cell activation, and potent anti-leukemia activities. ANT308 decreased CREB phosphorylation, a downstream signaling pathway of the VIP receptor, and stimulated granzyme B and perforin expression in CD8+ T cells from AML patients. Combiningin silicomodeling,in vitroT cell activation properties, andin vivoanti-leukemia activity has identified promising VIP-R antagonist candidates for further development as novel immunotherapies for AML, especially for patients with relapsed disease.

International journal of molecular sciences

Chemical Modifications to Enhance the Drug Properties of a VIP Receptor Antagonist (ANT) Peptide

Article

作者: Waller, Edmund K. ; Li, Jian-Ming ; Lester, Christina ; Wang, Yuou ; Passang, Tenzin ; Blakey, Simon B.

Antagonist peptides (ANTs) of vasoactive intestinal polypeptide receptors (VIP-Rs) are shown to enhance T cell activation and proliferation in vitro, as well as improving T cell-dependent anti-tumor response in acute myeloid leukemia (AML) murine models. However, peptide therapeutics often suffer from poor metabolic stability and exhibit a short half-life/fast elimination in vivo. In this study, we describe efforts to enhance the drug properties of ANTs via chemical modifications. The lead antagonist (ANT308) is derivatized with the following modifications: N-terminus acetylation, peptide stapling, and PEGylation. Acetylated ANT308 exhibits diminished T cell activation in vitro, indicating that N-terminus conservation is critical for antagonist activity. The replacement of residues 13 and 17 with cysteine to accommodate a chemical staple results in diminished survival using the modified peptide to treat mice with AML. However, the incorporation of the constraint increases survival and reduces tumor burden relative to its unstapled counterpart. Notably, PEGylation has a significant positive effect, with fewer doses of PEGylated ANT308 needed to achieve comparable overall survival and tumor burden in leukemic mice dosed with the parenteral ANT308 peptide, suggesting that polyethylene glycol (PEG) incorporation enhances longevity, and thus the antagonist activity of ANT308.

项与 ANT308 相关的新闻（医药）

2025-01-27

·PRNewswire

Seeking Investors: First-in-Class Immunotherapeutics for Cancer

ATLANTA, Jan. 27, 2025 /PRNewswire/ -- Cambium Oncology is pleased to share that their lead drug candidate, ANT308, recently demonstrated outstanding single-agent efficacy and safety in preclinical studies. The drug is mutation-agnostic, and the company observes no toxicity-limiting dosages. In addition to their Fast-Track SBIR NIH grant recently being funded for $2.4M, they have received a significant investment from OEP Innovations of Taiwan. ANT308 is a FIRST-IN-CLASS immunotherapeutic with broad therapeutic potential across hematologic malignancies and solid tumors with the potential to enhance response rates in cancers that are resistant to other treatments. The intellectual property portfolio is expansive and solid. We have no debt. MULTIPLE PROOFS-OF-CONCEPT: Leukemia and Pancreatic Cancers (1)Leukemia ANT308 has shown strong single-agent anti-leukemia activity in 2 mouse models. (2) Pancreatic cancer ANT308 has shown synergistic effects with anti-PD-1 checkpoint inhibitors in 3 pancreatic cancer models. ANT308 is a proprietary small-molecule antagonist that blocks VIP-receptor signaling on human T cells, overcoming immune suppression in the tumor microenvironment. About Cambium Oncology: Founded in 2018, Cambium Oncology, LLC is a Delaware-based biotech company developing next-generation immuno-oncology therapeutics to activate the immune system and overcome tumor resistance. Its proprietary pipeline focuses on checkpoint inhibitors and immune-modulating agents for pancreatic cancer, melanoma, and leukemia. • Founder: Ned Waller, MD, PhD, has launched two biotech companies and is board certified in medical oncology and internal medicine. Since 1995 he has been a practicing physician with Emory Healthcare. He specializes in bone marrow transplants for acute leukemia, myelodysplastic syndrome, myeloproliferative neoplasms, lymphoma, aplastic anemia, sickle cell disease and in the management of graft-versus-host disease (GVHD). He is also an expert in CAR T-cell therapy. • CEO: Gary G. Altman, PhD, an industry veteran with buy-side and sell-side transaction experience in biotech investments and company acquisitions. • Website: Cautionary Statement Regarding Forward-Looking Statements This press release contains forward-looking statements that involve known and unknown risks and uncertainties that may impact actual results. These statements are based on current expectations and are not guarantees of future performance. Media Contact: Gary Altman, [email protected], 305 484 7294, 13 Jan 2025 Logo - WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

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适应症	最高研发状态	国家/地区	公司	日期
胰腺导管腺癌	临床前	美国	Cambium Oncology LLC	2024-08-05
成人急性髓性白血病	临床前	美国	Emory University	2022-12-10
成人急性髓性白血病	临床前	美国	Cambium Oncology LLC	2022-12-10