[Translation] Phase III clinical trial of recombinant anti-EGFR human-mouse chimeric monoclonal antibody as first-line treatment for RAS/BRAF gene wild-type metastatic colorectal cancer

以FOLFIRI化疗方案为对照，评价CMAB009联合FOLFIRI化疗方案作为一线用药，治疗RAS/BRAF基因野生型、转移性结直肠癌患者的有效性与安全性。

[Translation]

Using FOLFIRI chemotherapy as a control, the efficacy and safety of CMAB009 combined with FOLFIRI chemotherapy as first-line treatment for patients with RAS/BRAF gene wild-type, metastatic colorectal cancer were evaluated.

Start Date19 Jan 2018

Sponsor / Collaborator

Shanghai Zhangjiang Biotechnology Co. Ltd.

NCT03206151 / Active, not recruitingPhase 3

Open, Randomized, Controlled, Multicenter Phase III Study Comparing CMAB009 Plus FOLFIRI Versus FOLFIRI Alone as First-line Treatment for Epidermal Growth Factor Receptor-expressing, RAS/BRAF Wild-type, Metastatic Colorectal Cancer

Drugs used against cancer work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as CMAB009, can block tumor growth in different ways. Giving combination chemotherapy together with CMAB009 as first treatment after diagnosis of a metastatic colorectal cancer（first-line treatment）may improve the treatment efficacy. However, it is not yet known whether giving combination chemotherapy together with CMAB009 is more effective than combination chemotherapy alone. This open-label trial investigates the effectiveness of CMAB009 in combination with a standard and effective chemotherapy FOLFIRI（5-Fluorouracil /Folinic acid plus Irinotecan）for RAS/BRAF wild-type, metastatic colorectal cancer in first-line setting, compared to the same chemotherapy alone.

Start Date12 Dec 2017

Sponsor / Collaborator

Taizhou Mabtech Pharmaceutical Co. Ltd.

CTR20130630 / Active, not recruitingPhase 2/3

重组抗EGFR单抗同步/序贯联合伊立替康化疗治疗转移性结直肠癌的随机对照、多中心、前瞻性II/III期临床研究

[Translation] A randomized, controlled, multicenter, prospective phase II/III clinical study of concurrent/sequential combination of recombinant anti-EGFR monoclonal antibody and irinotecan chemotherapy in the treatment of metastatic colorectal cancer

评价重组抗EGFR人鼠嵌合单克隆抗体注射液同步/序贯联合伊立替康两组治疗KRAS基因野生型、奥沙利铂和氟尿嘧啶类药物治疗无效的转移性结直肠癌的客观缓解率（ORR）、无进展生存期（PFS）和1年总生存率、安全性和耐受性。

[Translation]

To evaluate the objective response rate (ORR), progression-free survival (PFS), 1-year overall survival rate, safety, and tolerability of recombinant anti-EGFR human-mouse chimeric monoclonal antibody injection combined with irinotecan concurrently/sequentially in the treatment of metastatic colorectal cancer with wild-type KRAS gene that is refractory to oxaliplatin and fluorouracil.

Start Date-

Sponsor / Collaborator

Shanghai Zhangjiang Biotechnology Co. Ltd.

100 Clinical Results associated with Cetuximab biosimilar (Zhangjiang Biotech)

100 Translational Medicine associated with Cetuximab biosimilar (Zhangjiang Biotech)

100 Patents (Medical) associated with Cetuximab biosimilar (Zhangjiang Biotech)

Literatures (Medical) associated with Cetuximab biosimilar (Zhangjiang Biotech)

13 Jan 2023·Science immunology

Selective STING stimulation in dendritic cells primes antitumor T cell responses

Article

Author: Walters, Ian ; Bochnakian, Aurore ; Fiore, Frédéric ; Sedlik, Christine ; Akyol, Ramazan ; Hoffmann, Caroline ; Kramer, Robert ; Carlioz, Sylvain ; Malissen, Bernard ; Brousse, Carine ; Gerber-Ferder, Yohan ; Sirven, Philémon ; Manel, Nicolas ; Jneid, Bakhos ; Denizeau, Jordan ; Dalod, Marc ; Piaggio, Eliane ; Djacoto, Emeline ; Salmon, Hélène ; Delisle, Fabien

T cells that recognize tumor antigens are crucial for mounting antitumor immune responses. Induction of antitumor T cells in immunogenic tumors depends on STING, the intracellular innate immune receptor for cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) and related cyclic dinucleotides (CDNs). However, the optimal way to leverage STING activation in nonimmunogenic tumors is still unclear. Here, we show that cGAMP delivery by intratumoral injection of virus-like particles (cGAMP-VLP) led to differentiation of circulating tumor-specific T cells, decreased tumor regulatory T cells (T regs ), and antitumoral responses that synergized with PD1 blockade. By contrast, intratumoral injection of the synthetic CDN ADU-S100 led to tumor necrosis and systemic T cell activation but simultaneously depleted immune cells from injected tumors and induced minimal priming of circulating tumor-specific T cells. The antitumor effects of cGAMP-VLP required type 1 conventional dendritic cells (cDC1), whereas ADU-S100 eliminated cDC1 from injected tumors. cGAMP-VLP preferentially targeted STING in dendritic cells at a 1000-fold smaller dose than ADU-S100. Subcutaneous administration of cGAMP-VLP showed synergy when combined with PD1 blockade or a tumor T reg -depleting antibody to elicit systemic tumor-specific T cells and antitumor activity, leading to complete and durable tumor eradication in the case of tumor T reg depletion. These findings show that cell targeting of STING stimulation shapes the antitumor T cell response and identify a therapeutic strategy to enhance T cell–targeted immunotherapy.

04 Aug 2021·EMBO reportsQ1 · BIOLOGY

Inclusion of cGAMP within virus‐like particle vaccines enhances their immunogenicity

Q1 · BIOLOGY

Article

Author: Beveridge, Ryan ; Rijal, Pramila ; Liu, Xu ; Gilbert‐Jaramillo, Javier ; Russell, Rebecca A ; Rehwinkel, Jan ; Borrow, Persephone ; Townsend, Alain R ; Tan, Tiong K ; Chauveau, Lise ; Knight, Michael L ; Pedroza‐Pacheco, Isabela ; Frost, Joe N ; Drakesmith, Hal ; Partridge, Thomas ; Bridgeman, Anne

Cyclic GMP-AMP (cGAMP) is an immunostimulatory molecule produced by cGAS that activates STING. cGAMP is an adjuvant when administered alongside antigens. cGAMP is also incorporated into enveloped virus particles during budding. Here, we investigate whether inclusion of cGAMP within viral vaccine vectors enhances their immunogenicity. We immunise mice with virus-like particles (VLPs) containing HIV-1 Gag and the vesicular stomatitis virus envelope glycoprotein G (VSV-G). cGAMP loading of VLPs augments CD4 and CD8 T-cell responses. It also increases VLP- and VSV-G-specific antibody titres in a STING-dependent manner and enhances virus neutralisation, accompanied by increased numbers of T follicular helper cells. Vaccination with cGAMP-loaded VLPs containing haemagglutinin induces high titres of influenza A virus neutralising antibodies and confers protection upon virus challenge. This requires cGAMP inclusion within VLPs and is achieved at markedly reduced cGAMP doses. Similarly, cGAMP loading of VLPs containing the SARS-CoV-2 Spike protein enhances Spike-specific antibody titres. cGAMP-loaded VLPs are thus an attractive platform for vaccination.

01 Dec 2019·Cancer communications (London, England)Q1 · MEDICINE

CMAB009 plus irinotecan versus irinotecan‐only as second‐line treatment after fluoropyrimidine and oxaliplatin failure in KRAS wild‐type metastatic colorectal cancer patients: promising findings from a prospective, open‐label, randomized, phase III trial

Q1 · MEDICINE

ArticleOA

Author: Bi, Feng ; Hu, Xiaohua ; Wang, Liwei ; Cheng, Ying ; Ouyang, Xuenong ; Shi, Yuankai ; Sun, Yan ; He, Xiaohui ; Chen, Yigui ; Sun, Guoping ; Wang, Zhehai ; Liu, Wei ; Li, Yuhong ; Yao, Qiang ; Li, Jin ; Zheng, Rongsheng ; Zhang, Yiping ; Bai, Li ; Luo, Yi ; Liu, Yunpeng ; Qin, Shukui ; Xu, Jianming

Abstract:

Background:

The 5‐fluorouracil/leucovorin plus oxaliplatin (FOLFOX) regimen is the standard first‐line treatment for metastatic colorectal cancer (mCRC), however, the optimal second‐line regimen for KRAS wild‐type mCRC patients is still investigational. In this study, we aimed to determine the clinical efficacy and safety of CMAB009 plus irinotecan compared to irinotecan‐only as a second‐line regimen for treating KRAS wild‐type mCRC patients.

Methods:

Patients with KRAS wild‐type mCRC who had previously failed to respond to FOLFOX treatment were randomly assigned in a 2:1 ratio, to receive CMAB009 plus irinotecan or irinotecan‐only. Patients receiving irinotecan‐only were permitted to switch to CMAB009 therapy on disease progression and were grouped as the sequential‐CMAB009 arm. The primary endpoints were overall response rate (ORR) and median progression‐free survival (PFS). The secondary endpoints were median overall survival (OS), disease control rate (DCR), clinical benefit rate (CBR), and duration of response (DOR).

Results:

The CMAB009 plus irinotecan arm demonstrated significantly improved ORR (33.2% vs. 12.8%; P < 0.001) and longer median PFS (169 days vs. 95 days; P < 0.001) as compared to the irinotecan‐only arm. Patients receiving CMAB009 plus irinotecan also demonstrated improved DCR (80.1% vs. 65.2%, P < 0.001), CBR (30.0% vs. 14.6%, P < 0.001), and DOR (210 days vs. 109 days; P< 0.001) as compared to irinotecan‐only. However, patients treated with CMAB009 had an increased risk of skin rash (66.9% vs. 5.5%, P < 0.001) and paronychia (9.8% vs. 0.0%, P < 0.001). Anti‐drug antibodies (ADA) were detected in 3.6% of patients, and only 0.9% of patients who received CMAB009 experienced hypersensitivity reactions. In patients receiving sequential‐CMAB009 therapy after failure with irinotecan, their median PFS was 84 days (95% CI 65 to 113 days). The median OS was 425 days for patients receiving CMAB009 plus irinotecan and 401 days for those with sequential‐CMAB009 (P= 0.940).

Conclusions:

Treatment with CMAB009 plus irinotecan was found to be a superior second‐line regimen in comparison to irinotecan‐only in KRAS wild‐type mCRC patients. Further, switching to CMAB009 can be considered as an efficient third‐line of treatment after treatment failure with second‐line irinotecan‐only.Trial registrationClinicalTrials.gov: NCT01550055, retrospectively registered on March 9, 2012.

News (Medical) associated with Cetuximab biosimilar (Zhangjiang Biotech)

26 Jun 2024

·www.prnewswire.com

Simcere Zaiming Announce Approval of Cetuximab Beta in China by the NMPA

NANJING, China, June 26, 2024 /PRNewswire/ -- On June 25, 2024, Simcere Zaiming, an innovative oncology company and a subsidiary of Simcere Pharmaceutical Group (2096.HK), announced that Enlituo® (generic name: cetuximab beta injection), a new generation anti-epidermal growth factor receptor (EGFR) antibody drug developed in collaboration with Mabpharm Limited (2181.HK), has recently received approval from the China National Medical Administration (NMPA) for marketing. Enlituo® is indicated for use in combination with the FOLFIRI regimen as a first-line treatment for RAS/BRAF wild-type metastatic colorectal cancer (mCRC). According to the 'Cancer Incidence and Mortality in China, 2022' by the National Cancer Center, colorectal cancer ranks as the second most common cancer in China. Annually, there are 1.571 million new cases and 240,000 deaths, imposing a substantial disease burden on the society. When colorectal cancer patients develop metastasis, the primary treatment options often include chemotherapy and targeted drugs. Previous clinical studies have demonstrated the effectiveness of EGFR-targeting antibody drugs in treating malignant tumors, particularly mCRC, in patients without RAS/BRAF mutations (wild-type). Enlituo® (cetuximab beta, originally known as CMAB009) is a recombinant EGFR monoclonal antibody developed independently in China. Classified as a 2.4 class modified biological new drug, cetuximab beta is prepared using a proprietary protein expression technique, effectively avoiding glycosylation modification that may lead to hypersensitivity. Enlituo® received approval based on robust evidence from a phase 2/3 study and a phase 3 confirmatory clinical trial. In an open-label, randomized, controlled, multicenter, prospective phase 3 study, 505 subjects with RAS/BRAF wild-type mCRC were treated and analyzed. Clinical data revealed that combining cetuximab beta with FOLFIRI significantly extended progression-free survival (PFS) compared to FOLFIRI alone (13.133 months vs. 9.567 months, P = 0.004). Additionally, the combination increased the objective response rate (ORR) (69.1% vs. 42.3%, P < 0.001) and overall survival (OS) (2.322 years vs. 1.900 years, P = 0.024). Dr. Renhong Tang, Chairman of Simcere Zaiming, emphasized Enlituo®'s unique clinical value in targeted therapy: "Its initial indication for colorectal cancer addresses a large patient population. The product synergizes well with Simcere Zaiming's existing offerings, and efforts are underway to accelerate its commercialization, benefiting more cancer patients." Dr. Hao Wang, Chief Executive Officer of Mabpharm, expressed excitement as Enlituo® bridged the gap in colorectal cancer treatment with domestically developed EGFR-targeted drugs. "This provides clinicians and patients with updated therapeutic options. By collaborating with Simcere Zaiming's Marketing Team, we are able to rapidly realize the clinical value of Enlituo®, benefiting hundreds of thousands of patients in China with an effective and affordable biological new drug. " Enlituo represents the first EGFR monoclonal antibody drug developed in China with independent intellectual property rights that are approved for the first-line treatment of mCRC. The successful launch of Enlituo® will provide high quality and affordable biological targeted remedy for Chinese cancer patients. In March 2023, the drug marketing application of Enlituo® was accepted by the NMPA. On August 18, 2023, the Group entered into a cooperation agreement with Mabpharm, pursuant to which the Group obtained the exclusive commercial rights in respect of Enlituo® in Chinese mainland. About Mabpharm Mabpharm (stock code: 2181) focuses on the development of monoclonal antibodies and has an experienced R&D team, multiple core technologies, leading domestic large-scale antibody preparation system and excellent quality control system. Mabpharm strives to bring high quality and affordable innovative biologics through its efficient R&D system and low-cost pharmaceutical production capability to the market, and develops various therapeutic products by fully utilizing its extensive R&D experience. About Simcere Zaiming Simcere Zaiming, an oncology-centric biopharmaceutical subsidiary of Simcere Pharmaceutical Group Limited (HKEX: 2096), was established in 2023. The company is devoted to crafting groundbreaking therapies aimed at fulfilling the unmet clinical needs of cancer patients globally. With a robust and innovative R&D pipeline featuring distinct clinical assets, Simcere Zaiming has successfully launched several products in China, including COSELA®, Endostar®, and Envafolimab. The company is determined to deliver potentially transformative treatment options to cancer patients worldwide through its internal R&D, manufacturing, and commercialization capabilities, complemented by strategic collaborations with leading partners in the field of innovative cancer therapeutics. SOURCE Simcere

Drug ApprovalPhase 3License out/inClinical ResultCSCO

24 Aug 2022

·www.sciencedaily.com

DNA guardians out of control

Our own immune system can become the enemy when mechanisms that are actually protective get out of control. In ANCA-associated vasculitis, excessive inflammatory reactions lead to pulmonary hemorrhages that can be fatal if left untreated. Researchers have deciphered a mechanism in mice and patients that leads to the severe disease. Our own immune system can become the enemy when mechanisms that are actually protective get out of control. In ANCA-associated vasculitis, excessive inflammatory reactions lead to pulmonary hemorrhages that can be fatal if left untreated. Researchers at the University of Bonn, together with colleagues from Germany, the Netherlands, Switzerland and England, have deciphered a mechanism in mice and patients that leads to the severe disease. The results are now published in the Journal of Experimental Medicine. In ANCA-associated vasculitis, there is severe inflammation of the smaller and medium-sized blood vessels in the lungs. In addition, the skin and kidneys may also be affected. ANCA stands for "anti-neutrophil cytoplasmic antibodies," which are antibodies produced by the body that target its own white blood cells. It is a rare, severe autoimmune disease that is often fatal if left untreated due to pulmonary hemorrhage. Therapy involves the administration of drugs that suppress the immune system. Recently, attempts have also been made to block the inflammatory cascade with inhibitors. "The challenge in finding new therapies is that very little is known about the mechanisms that trigger the disease," says Prof. Natalio Garbi of the Institute of Molecular Medicine and Experimental Immunology (IMMEI) at Bonn University Hospital. Together with colleagues from Germany, the Netherlands, Switzerland and the United Kingdom, the scientists have now discovered a mechanism responsible for the development of the disease in the form of the cGAS/STING/IFN-I signaling pathway. "We were able to show in experiments with mice that the symptoms of this autoimmune disease -- such as pulmonary hemorrhage -- improve when this signaling pathway is blocked with drugs," says first author and doctoral student Nina Kessler from Natalio Garbi's team. The study involved 31 patients with ANCA vasculitis and, as controls, 57 healthy individuals as well as a novel mouse model. Stray DNA Normally, the genetic material DNA is located in the nucleus or mitochondria of cells. But if pathogens such as bacteria or viruses have taken up residence in the cell, they may leave behind a DNA trail in the cytosol that is detected by a special sensor called cGAS. This sentinel produces a molecule called cGAMP, which in turn activates the STING molecule. As a result, type 1 interferon (IFN-I) production occurs, leading to strong inflammation. This should prevent the pathogens from multiplying and even drive heavily infected cells into cellular suicide. "It becomes problematic when these mechanisms are not triggered by pathogens but by our own cellular DNA," Garbi explains. Then the cGAS/STING/IFN-I signaling pathway leads to cell death. "In our study, we show that for reasons still unknown, DNA is released from the cell nucleus and activates the signaling pathway. This leads to blood vessel destruction and frank hemorrhage," says Garbi, a member of the ImmunoSensation2 cluster of excellence at the University of Bonn. Researchers recreate disease development in mice The researchers recreated the most important steps of disease development in mice. To do this, they administered pathogenic autoantibodies to the animals and introduced bacterial products into their lungs to mimic an infection such as occurs during an ANCA vasculitis flare. The mice then developed lung disease and hemorrhage. At various points, the researchers interrupted the cGAS/STING/IFN-I signaling chain by "silencing" certain genes -- for example, for IFN-I or for certain macrophages of the immune system. From the results in the mice, the researchers conclude that it is indeed an overactivation of cGAS/STING by DNA misplaced in the cell that leads to the severe disease. Elevated blood levels of IFN-I and cGAMP in the patients studied suggest that the out-of-control DNA guardian in the cells is responsible for disease progression. "Immune cells are both friends and foes of the disease," says Susanne Viehmann, PhD from the IMMEI lab of Prof. Christian Kurts. Macrophages originated from the blood produce the inflammatory molecule IFN-I, which drives the disease. At the same time, a different type of macrophages in the alveoli eat up red blood cells that leak out of the vessels, thereby reducing pro-inflammatory factors. "By better understanding the molecular processes of severe ANCA vasculitis, we have been able to identify potential drug targets in the preclinical model that are already approved for other diseases," Garbi says. However, more intensive research is still needed, he adds.

Antibody

100 Deals associated with Cetuximab biosimilar (Zhangjiang Biotech)

External Link

KEGG	Wiki	ATC	Drug Bank
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R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
RAS/BRAF Wild Type Colorectal Cancer	CN	Taizhou Mabtech Pharmaceutical Co. Ltd.	18 Jun 2024

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Colorectal Cancer	NDA/BLA	CN	Taizhou Mabtech Pharmaceutical Co. Ltd.	14 Mar 2023
Metastatic Colorectal Carcinoma	Phase 3	CN	Shanghai Zhangjiang Biotechnology Co. Ltd.	23 Oct 2013

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01550055 (CRC009, Pubmed \| Cancer Commun (Lond)) Manual	Phase 3	KRAS Wild-type Colorectal Cancer Second line KRAS Wild-type	1,077	irinotecan+CMAB009	tvskxvwdzw(ccnokzgupp) = yxpomrinoj yyjxzqwihg (bnrknegtsw ) View more	Superior	24 May 2019
				irinotecan	tvskxvwdzw(ccnokzgupp) = kuyyrphibh yyjxzqwihg (bnrknegtsw ) View more
NCT01550055 (ZJBIO009, ASCO2017)	Phase 3	KRAS Wild-type Colorectal Cancer \| Metastatic Colorectal Carcinoma Second line	512	CMAB009 plus irinotecanCMAB009 plus irinotecan	krwgxnhcun(hidethyezl) = dcndvkbnvs fndmltxrkg (fznoywytsk ) View more	Positive	30 May 2017
				Irinotecan alone	krwgxnhcun(hidethyezl) = gvvrrcfrmx fndmltxrkg (fznoywytsk ) View more

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