A Phase 1, First-in-Human Study of NTX-1088, a Monoclonal Antibody Targeting the Poliovirus Receptor (PVR, CD155), as Monotherapy and Combined With Pembrolizumab, in Patients With Advanced Solid Malignancies

This is a Phase 1,open-label, multi-center, first-in-human, 2-part (Part 1: dose escalation and Part 2: expansion) study, evaluating multiple doses and schedules of intravenously (IV) administered NTX-1088, with or without pembrolizumab, in patients with advanced solid malignancies (i.e., locally advanced or metastatic).

开始日期2022-09-01

申办/合作机构

Nectin Therapeutics Ltd.初创企业

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100 项与 NTX-1088 相关的临床结果

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100 项与 NTX-1088 相关的转化医学

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100 项与 NTX-1088 相关的专利（医药）

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项与 NTX-1088 相关的文献（医药）

2023-01-01·Frontiers in oncology

Diverging prognostic effects of CD155 and CD73 expressions in locally advanced triple-negative breast cancer.

Article

作者: Saip, Pinar ; Aydiner, Adnan ; Emiroglu, Selman ; Yavuz, Ekrem ; Tukenmez, Mustafa ; Igci, Abdullah ; Muslumanoglu, Mahmut ; Ozmen, Vahit ; Bayram, Aysel ; Cabioglu, Neslihan ; Onder, Semen ; Oner, Gizem ; Karatay, Huseyin

Background:

Immune checkpoint inhibition, combined with novel biomarkers, may provide alternative pathways for treating chemotherapy-resistant triple-negative breast cancer (TNBC). This study investigates the expression of new immune checkpoint receptors, including CD155 and CD73, which play a role in T and natural killer (NK) cell activities, in patients with residual TNBC after neoadjuvant chemotherapy (NAC).

Methods:

The expression of biomarkers was immunohistochemically examined by staining archival tissue from surgical specimens (n = 53) using specific monoclonal antibodies for PD-L1, CD155, and CD73.

Results:

Of those, 59.2% (29/49) were found to be positive (>1%) for PD-L1 on the tumour and tumour-infiltrating lymphocytes (TILs), while CD155 (30/53, 56.6%) and CD73 (24/53, 45.3%) were detected on tumours. Tumour expressions of CD155 and CD73 significantly correlated with PD-L1 expression on the tumour (p = 0.004 for CD155, p = 0.001 for CD73). Patients with CD155 positivity ≥10% were more likely to have a poor chemotherapy response, as evidenced by higher MDACC Residual Cancer Burden Index scores and Class II/III than those without CD155 expression (100% vs 82.6%, p = 0.03). At a median follow-up time of 80 months (range, 24-239), patients with high CD73 expression showed improved 10-year disease-free survival (DFS) and disease-specific survival (DSS) rates compared to those with low CD73 expression. In contrast, patients with CD155 (≥10%) expression exhibited a decreasing trend in 10-year DFS and DSS compared to cases with lower expression, although statistical significance was not reached. However, patients with coexpression of CD155 (≥10%) and low CD73 were significantly more likely to have decreased 10-year DFS and DSS rates compared to others (p = 0.005).

Conclusion:

These results demonstrate high expression of CD73 and CD155 in patients with residual tumours following NAC. CD155 expression was associated with a poor response to NAC and poor prognosis in this chemotherapy-resistant TNBC cohort, supporting the use of additional immune checkpoint receptor inhibitor therapy. Interestingly, the interaction between CD155 and CD73 at lower levels resulted in a worse outcome than either marker alone, which calls for further investigation in future studies.

2022-04-01·Frontiers of medicine3区 · 医学

Multi-target combinatory strategy to overcome tumor immune escape

3区 · 医学

Review

作者: Yu, Yingyan

Immune therapy has become the fourth approach after surgery, chemotherapy, and radiotherapy in cancer treatment. Many immune checkpoints were identified in the last decade since ipilimumab, which is the first immune checkpoint inhibitor to cytotoxic T-lymphocyte associated protein 4, had been approved by the US Food and Drug Administration (FDA) for the treatment of unresectable or metastatic melanoma in 2011. The use of several antibody drugs that target PD1/PD-L1 for various cancer treatments has been approved by the FDA. However, fewer people are benefitting from immune checkpoint inhibitor treatment in solid cancers. Approximately 80% of patients do not respond appropriately because of primary or acquired therapeutic resistance. Along with the characterization of more immune checkpoints, the combinatory treatment of multiimmune checkpoint inhibitors becomes a new option when monotherapy could not receive a good response. In this work, the author focuses on the combination therapy of multiple immune checkpoints (does not include targeted therapy of oncogenes or chemotherapy), introduces the current progression of multiple immune checkpoints and their related inhibitors, and discusses the advantages of combination therapy, as well as the risk of immune-related adverse events.

2021-09-01·International journal of radiation oncology, biology, physics2区 · 医学

Radiation-Induced Autophagy in Human Pancreatic Cancer Cells is Critically Dependent on G2 Checkpoint Activation: A Mechanism of Radioresistance in Pancreatic Cancer

2区 · 医学

Article

作者: Hasegawa, Sumitaka ; Anko, Mayuka ; Matsumoto, Ken-Ichiro ; Ohara, Maki ; Suzuki, Motofumi

PURPOSE:

Autophagy and cell-cycle checkpoints act in concert to confer cellular radioresistance. We investigated the functional interaction between radiation-induced autophagy and G2 checkpoint activation in highly radioresistant human pancreatic ductal adenocarcinoma (PDAC) cells.

METHODS AND MATERIALS:

Four human PDAC cell lines (MIA PaCa-2, KP-4, Panc-1, and SUIT-2) were analyzed. These cells were first irradiated using x-rays, and their cell cycle status, autophagy, and cell cycle checkpoint marker expression and ATP production levels were evaluated. Autophagic flux assays and siRNA knockdown were used to evaluate autophagy activity. Double thymidine block experiments were performed to synchronize the cells. Two inhibitors (MK-1775 and SCH 900776) were used to attenuate G2 checkpoint activation. Cell survival assays and animal experiments were performed to evaluate the radiosensitizing effects of the G2 checkpoint inhibitors.

RESULTS:

Autophagy and G2/M accumulation were synchronously induced in human PDAC cells with an activated G2 checkpoint at 12 hours after x-ray irradiation of 6 Gy. Radiation-induced autophagy produced the ATP levels required for cell survival. Double thymidine block experiments revealed that no autophagy occurred in cells that were solely in G2 phase. MK-1775 or SCH 900776 exposure attenuated not only G2 checkpoint activation but also postirradiation autophagy, indicating the dependence of radiation-induced autophagy on an activated G2 checkpoint. The inhibitors demonstrated a higher radiosensitizing effect in the PDAC cells than the autophagy inhibitor chloroquine. MK-1775 in combination with x-rays significantly suppressed the tumor growth of MIA PaCa-2 xenografts compared with other treatment groups, including radiation or drug exposure alone, to enhance the radiosensitivity of PDAC cells in vivo.

CONCLUSIONS:

Biological crosstalk exists between the G2 checkpoint activation and radiation-induced autophagy processes that are believed to independently contribute to the radioresistance of human PDAC cells. These findings have important implications for the development of future radiation therapy strategies for PDAC.

项与 NTX-1088 相关的新闻（医药）

2024-07-25

·PRNewswire

Nectin Therapeutics Licenses Novel Antibodies to Immunome

– Exclusive worldwide license agreement for antibodies against undisclosed target JERUSALEM, July 25, 2024 /PRNewswire/ -- Nectin Therapeutics, Ltd., a biotechnology company developing novel immunotherapies and antibody drug conjugates (ADC) to address tumor resistance, today announced a global, exclusive license agreement with Immunome Inc. (Nasdaq: IMNM), a biotechnology company focused on developing first-in-class and best-in-class targeted cancer therapies. Under the terms of the license, Immunome received exclusive rights to a panel of antibodies targeting an undisclosed target. "This agreement allows Nectin to realize value while further pursuing and enabling the focus on our first-in-class anti-PVR program (NTX1088) through its ongoing clinical study in tumor types with high unmet need as well as advance our novel ADCs into clinical development. Immunome's leadership team's track record of developing and commercializing novel ADC therapies makes it an ideal partner to advance these promising assets," said Fabian Tenenbaum, Chief Executive Officer of Nectin Therapeutics. "Immunome believes the next generation of transformative antibody drug conjugates will address novel targets by pairing high-quality antibodies with innovative linker-payload technology," said Clay Siegall, PhD, President and Chief Executive Officer of Immunome. "We appreciate the work Nectin has done on these antibodies and look forward to advancing them further." Under the terms of the agreement, Nectin granted Immunome an exclusive, worldwide, all-fields license to monoclonal antibodies that are directed to a single undisclosed target. Immunome will be responsible for the research, development, manufacturing and commercialization of products incorporating these antibodies. Nectin will receive an upfront payment and will be eligible for milestones and royalties. About Nectin Therapeutics, LTD. Nectin Therapeutics is a clinical stage biotechnology company devoted to transforming the lives of cancer patients by leveraging unique insights into Nectin pathways to develop the next generation of immune oncology (IO) therapies and antibody drug conjugates (ADCs). The company's differentiated therapies have the potential to set new standards for efficacy and patient response rates across various difficult-to-treat cancers. Nectin's technology addresses major escape mechanisms of current IO therapies through a diverse pipeline of novel monoclonal antibodies and antibody drug conjugates (ADCs). It has a world-class scientific and management team with deep experience in oncology drug development and successful track records in building biotechnology companies and developing innovative therapies. Nectin Therapeutics is a venture-backed, privately held company, funded by aMoon Fund, Peregrine Ventures, IBF, Integra Holdings, the Myeloma Investment Fund (MIF), GIBF and the Cancer Focus Fund. Nectin Contact: Fabian Tenenbaum Chief Executive Officer [email protected] +1 201 218-1774 SOURCE Nectin Therapeutics

引进/卖出免疫疗法抗体药物偶联物

2024-07-25

·Firstwordpharma

Immunome bets on Nectin's antibodies for next-gen ADCs

Immunotherapies and antibody-drug conjugates (ADCs) are all the rage, although many of the most successful cancer drugs of the last two decades pursue only a small set of proven targets.In a move that could expand this limited repertoire, Nectin Therapeutics said Thursday it has inked an agreement granting Immunome exclusive rights to a panel of antibodies directed against a "first-in-class" target – although what that target is exactly is being kept under wraps for now.Immunome is led by industry veteran Clay Siegall, who co-founded ADC pioneer Seagen (then known as Seattle Genetics) back in 1997. Seagen has since gone on to be acquired by Pfizer to the tune of $43 billion.Underexplored targets"The next generation of transformative antibody-drug conjugates will address novel targets by pairing high-quality antibodies with innovative linker-payload technology," Siegall said. "We appreciate the work Nectin has done on these antibodies and look forward to advancing them further."The collaboration aligns with Immunome's approach of pursuing underexplored targets, a strategy the company believes will drive the next wave of therapies in oncology. For more on the space, see – Vital Signs: Tracking the new converts to ADCs.Commenting on the alliance, Nectin CEO Fabian Tenenbaum told FirstWord that the target in question is a "specific antigen that is differentially expressed on a number of tumours that currently have significant unmet need, and [we] have seen really compelling evidence from our preclinical work in terms of both in vitro and in vivo efficacy, with a number of next-generation payload compounds."Tenenbaum also shed light on why Nectin chose to partner with Immunome, noting that Siegall "obviously has a tremendous track record in building Seagen," as do other senior team members at Immunome who have experience "developing and commercialising novel antibody-drug conjugates."While financial details of the agreement remain confidential, Nectin will receive an upfront payment and also be eligible for milestones and royalties. Meanwhile, Tenenbaum hinted at the potential timeline for development, saying "we do think that an IND (investigational new drug) filing and a Phase I can start within the next 24 months. That's a very reasonable timeline."The agreement doesn't include Nectin's internal pipeline candidates, but Tenenbaum indicated that the deal would bring capital to allow it to move some of its in-house assets forward.The company's most advanced project, NTX1088, is a monoclonal antibody directed against the PVR (CD155) immune checkpoint, and is currently in Phase I for solid tumours both as monotherapy and in combination with Merck & Co.'s PD-1 inhibitor Keytruda (pembrolizumab). Nectin is also advancing NTX2R13, targeting CD112R (PVRIG), which is in the IND-enabling phase.It is working on a trio of ADCs as well: one targeting Nectin2 (NTX1107) for both solid and haematological cancers, another directed against Nectin4 (NTX1105) and a third against PVR (NTX8090), both for solid tumours.

免疫疗法抗体药物偶联物临床1期并购引进/卖出

2024-05-06

·PRNewswire

GIBF invests $10 Million in Nectin Therapeutics to Advance Novel Pipeline of First-in-Class Immunotherapies and Antibody Drug Conjugates

Proceeds from financing to support ongoing clinical development of lead program targeting PVR as well as IND-enabling activities for multiple ADC candidates TEL AVIV, Israel, May 6, 2024 /PRNewswire/ -- Guangzhou-Israel Biotechnology Fund (GIBF) announced today that it has invested $10 million in Nectin Therapeutics Ltd. Nectin is a biotechnology company developing novel targeted immunotherapies that address resistance to approved immune oncology treatments. The funds will be used to continue the development of Nectin's portfolio of novel immuno-oncology products, including the advancement of Nectin's ongoing NTX1088 global Phase 1 clinical trial targeting PVR and the preclinical development of its anti-drug conjugate (ADC) portfolio. Nectin is a clinical stage biotechnology company devoted to transforming the lives of cancer patients by leveraging unique insights into the nectin pathways to develop the next generation of immune oncology (IO) therapies. The company's differentiated therapies have the potential to set new standards for efficacy and patient response rates across various difficult-to-treat cancers. Nectin's technology addresses major escape mechanisms of current IO therapies through a diverse pipeline of novel monoclonal antibodies and antibody-drug-conjugates. It has a world-class scientific and management team with deep experience in oncology drug development and a successful track record in building biotechnology companies and developing innovative therapies. Nectin is a venture-backed, privately held company, funded by aMoon Fund, Peregrine Ventures, IBF, Integra Holdings, Myeloma Investment Fund (MIF), and Cancer Focus Fund. NTX1088 is Nectin's First-in-Class lead candidate - a highly potent monoclonal antibody directed against PVR (CD155), a transmembrane protein expressed on cancer cells and associated with resistance to PD1 and PDL1 immune checkpoint inhibitors. PVR blockade by NTX1088 is the first and only therapeutic approach aiming at restoring the antitumor immune activity of DNAM1 (CD226). DNAM1 is a cell surface glycoprotein, central to the function of T and NK cells, that is suppressed by PVR on tumor cells. Restoring the expression and activation of DNAM1 by blocking PVR results in increased antitumor activity from T and NK cells. PVR blockade by NTX1088 further stimulates an antitumor immune response by preventing the suppressing signaling of several immune checkpoint receptors, including TIGIT and CD96. PVR is overexpressed in many solid tumors across different cancer indications, including lung, colorectal, liver, ovarian, breast, adrenal, pancreatic, uterine, head and neck, gastric and esophageal cancers. High PVR expression is associated with poor prognosis and with resistance to PD1 and PDL1 blockade, making PVR an attractive target for both monotherapy and in combination with PD1 blockers, as is currently being clinically evaluated in the combination of NTX1088 and KEYTRUDA® (pembrolizumab). "Nectin is working to usher in a new era of innovative immune-mediated cancer medicines and we are excited to back this important mission and team," said Professor Shlomo Noy, Managing Partner and Chief Medical Officer of GIBF. "We have been following the company closely as it continues to make meaningful progress across its portfolio as it develops transformational therapies that can improve the lives of many cancer patients and their treatment outcomes." "We are grateful for the support from GIBF which reflects the rapid advancement of our anti-PVR clinical program as well as the progress in our development of several ADC candidates," said Fabian Tenenbaum, CEO of Nectin Therapeutics. "With this new investment we are looking forward to completing both the dose-escalation and dose-expansion trials for NTX1088 and continue our IND-enabling activities of our ADC assets. We value GIBF's commitment to our mission of developing life-saving therapies and look forward to advancing innovative medicines to improve the lives of cancer patients." Contact: GIBF Avner Lushi Chief Executive Officer [email protected] SOURCE The Guangzhou Sino-Israel Biotech Investment Fund (GIBF)

免疫疗法抗体药物偶联物临床1期

100 项与 NTX-1088 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
局部晚期恶性实体瘤	临床1期	美国	Nectin Therapeutics Ltd.初创企业	2022-09-01
局部晚期恶性实体瘤	临床1期	以色列	Nectin Therapeutics Ltd.初创企业	2022-09-01
肿瘤转移	临床1期	美国	Nectin Therapeutics Ltd.初创企业	2022-09-01
肿瘤转移	临床1期	以色列	Nectin Therapeutics Ltd.初创企业	2022-09-01
实体瘤	临床前	加拿大	Northern Biologics, Inc.初创企业	-