Synthesis, characterization, and targeted chemotherapy of SCT200-linker-monomethyl auristatin E conjugates

Hu, Xinyue; Jiang, Hailun; Bai, Wenjing; Liu, Xiujun; Qin, Miao; Wang, Linlin; Jin, Jie; Cui, A-Long; Li, Rui; Li, Zhuorong

doi:10.1016/j.ejmech.2021.113297

Cited by 3 publications

(4 citation statements)

References 28 publications

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“…This may open other liver and organ therapeutic applications benefiting from the blood/lymphatic stability and intracellular release properties. The PABC self-immolative linker segment removal was critical to reducing mouse carboxylesterase cleavage and subsequent blood exposure of TQ via the SC route (80)(81)(82)(83)(84). This pSVCTQ design reduced the C max of TQ in blood by over 75% and the blood AUC over 14 days by more than 50%.…”

Section: Discussionmentioning

confidence: 99%

Liver-targeted polymeric prodrugs delivered subcutaneously improve tafenoquine therapeutic window for malaria radical cure

Pottenger,

Roy,

Srinivasan

et al. 2024

Sci. Adv.

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Approximately 3.3 billion people live with the threat of Plasmodium vivax malaria. Infection can result in liver-localized hypnozoites, which when reactivated cause relapsing malaria. This work demonstrates that an enzyme-cleavable polymeric prodrug of tafenoquine addresses key requirements for a mass administration, eradication campaign: excellent subcutaneous bioavailability, complete parasite control after a single dose, improved therapeutic window compared to the parent oral drug, and low cost of goods sold (COGS) at less than $1.50 per dose. Liver targeting and subcutaneous dosing resulted in improved liver:plasma exposure profiles, with increased efficacy and reduced glucose 6-phosphate dehydrogenase–dependent hemotoxicity in validated preclinical models. A COGS and manufacturability analysis demonstrated global scalability, affordability, and the ability to redesign this fully synthetic polymeric prodrug specifically to increase global equity and access. Together, this polymer prodrug platform is a candidate for evaluation in human patients and shows potential for P. vivax eradication campaigns.

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Section: Discussionmentioning

confidence: 99%

Liver-targeted polymeric prodrugs delivered subcutaneously improve tafenoquine therapeutic window for malaria radical cure

Pottenger,

Roy,

Srinivasan

et al. 2024

Sci. Adv.

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“…Other vedotin-based ADCs are currently under clinical trials, such as ladiratuzumab vedotin [ 82 ], telisotuzumab vedotin [ 83 ], lifastuzumab vedotin [ 84 ], PSMA ADC [ 85 ], TAK-264 [ 86 ], or MRG002 [ 87 ], which target LIV-1, MET, NaPi2b, PSMA, GCC and HER2 receptors, respectively. On the other hand, other ADCs of this class are in preclinical stages, such as the cases of the ADCs with the antibodies SCT-200 [ 88 ], a fully humanized anti-epidermal growth factor receptor (EGFR), or MCDT2219A, an anti-CD22 monoclonal IgG1 antibody [ 89 ]. These examples, like many others, are an indication of the tremendous interest in this therapeutic strategy against cancer, resulting in a flurry of activity directed toward the development of ADCs with auristatins as payloads within the relatively short time since the approval of Adcetris.…”

Section: Chemistry and Biology Of Marine Antibody-drug Conjugatesmentioning

confidence: 99%

Antibody-Drug Conjugates Containing Payloads from Marine Origin

et al. 2022

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Antibody-drug conjugates (ADCs) are an important class of therapeutics for the treatment of cancer. Structurally, an ADC comprises an antibody, which serves as the delivery system, a payload drug that is a potent cytotoxin that kills cancer cells, and a chemical linker that connects the payload with the antibody. Unlike conventional chemotherapy methods, an ADC couples the selective targeting and pharmacokinetic characteristics related to the antibody with the potent cytotoxicity of the payload. This results in high specificity and potency by reducing off-target toxicities in patients by limiting the exposure of healthy tissues to the cytotoxic drug. As a consequence of these outstanding features, significant research efforts have been devoted to the design, synthesis, and development of ADCs, and several ADCs have been approved for clinical use. The ADC field not only relies upon biology and biochemistry (antibody) but also upon organic chemistry (linker and payload). In the latter, total synthesis of natural and designed cytotoxic compounds, together with the development of novel synthetic strategies, have been key aspects of the consecution of clinical ADCs. In the case of payloads from marine origin, impressive structural architectures and biological properties are observed, thus making them prime targets for chemical synthesis and the development of ADCs. In this review, we explore the molecular and biological diversity of ADCs, with particular emphasis on those containing marine cytotoxic drugs as the payload.

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“…Moreover, SCT200 can stimulate the immune effects of complement-dependent cytotoxicity (CDC) and ADCC to kill tumor cells through Fc functional regions, with a killing of more than 30%. Previous studies have shown that the pharmacodynamic effects of SCT200 in vivo and in vitro correlated with its mechanism of blocking the EGFR signal pathway 20 . Regarding the safety of SCT200, the toxic target organs are mainly the skin and gastrointestinal system.…”

Section: Introductionmentioning

confidence: 99%

“…SCT200 is a novel recombinant humanized anti-human EGFR monoclonal antibody developed by Sinocelltech Ltd. (Beijing, China). Mechanistically, SCT200 suppresses the proliferation of cancerous cells by effectively blocking ligands such as EGF and inhibiting the activation of the EGFR signal pathway 20 . SCT200 shows significantly better antibody-dependent cell mediated-cytotoxicity (ADCC) than cetuximab.…”

Section: Introductionmentioning

confidence: 99%

Safety and efficacy of anti-EGFR monoclonal antibody (SCT200) as second-line therapy in advanced esophageal squamous cell carcinoma

Bai

2022

Cancer Biol Med

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Objective: The mainstay treatment of esophageal squamous cell carcinoma (ESCC) involves chemotherapy and immunotherapy.However, alternative therapies are required for patients who are refractory or intolerant to existing therapies. Methods: In this single-arm, multicenter, open-label phase Ib study, 30 patients received an intravenous infusion of SCT200, an antiepidermalgrowth factor receptor (EGFR) monoclonal antibody, 6.0 mg/kg once a week for 6 weeks, followed by 8.0 mg/kg once every2 weeks until disease progression or intolerable toxicity. The primary endpoint was the objective response rate (ORR). The secondaryendpoints were progression-free survival (PFS), overall survival (OS), and safety. Results: Thirty patients were enrolled between July 2018 and May 2019. The ORR was 16.7% (95% CI: 5.6%–34.7%). The medianPFS and OS were 3.1 months (95% CI: 1.5–4.3) and 6.8 months (95% CI: 4.7–10.1), respectively. A numerical difference without anystatistical significance in ORR was observed in patients with different EGFR expressions (= 50%: 25.0% vs. < 50%: 0%, P = 0.140)or TP53 mutation abundance (< 10%: 23.8% vs. = 10%: 0%, P = 0.286). Improved median PFS (3.4 vs. 1.4 months, P = 0.006) andOS (8.0 vs. 4.2 months, P = 0.027) were associated with TP53 mutation abundance of < 10%. The most common treatment-relatedadverse events of grade 3 or 4 (occurring in = 2 patients) were hypomagnesemia [7 (23.3%)] and rash [2 (6.7%)]. No treatmentrelateddeath occurred. Conclusions: SCT200 monotherapy as the second- or further-line treatment for advanced ESCC showed favorable efficacy, with anacceptable safety profile. TP53 mutation abundance might serve as a potential predictive biomarker.

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Synthesis, characterization, and targeted chemotherapy of SCT200-linker-monomethyl auristatin E conjugates

Cited by 3 publications

References 28 publications

Liver-targeted polymeric prodrugs delivered subcutaneously improve tafenoquine therapeutic window for malaria radical cure

Liver-targeted polymeric prodrugs delivered subcutaneously improve tafenoquine therapeutic window for malaria radical cure

Antibody-Drug Conjugates Containing Payloads from Marine Origin

Safety and efficacy of anti-EGFR monoclonal antibody (SCT200) as second-line therapy in advanced esophageal squamous cell carcinoma

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