Preclinical Studies of OBI-999: A Novel Globo H–Targeting Antibody–Drug Conjugate

Yang, Ming-Chen; Shia, Chi-Sheng; Li, Wan-Fen; Wang, Chun-Chung; Chen, I-Ju; Huang, Tseng-Chieng; Chen, Yu-Jung; Chang, Hui‐Wen; Lu, Chi-Huan; Wu, Yueh-Chin; Wang, Nan-Hsuan; Yu, Cheng-Der; Lai, Ming‐Tain

doi:10.1158/1535-7163.mct-20-0763

Cited by 18 publications

(8 citation statements)

References 34 publications

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“…Disease stabilization was noted in several patients with advanced metastatic cancer who had previously experienced progressive disease on standard treatments. Because Globo H is overexpressed in approximately 50% of pancreatic tumors 7 and patients with this disease need additional treatment options, we are conducting a phase II study of OBI-999 in patients with advanced/metastatic pancreatic cancer, as well as with hepatocellular carcinoma, and other epithelial carcinomas. Patients with pancreatic cancer are eligible if their disease has progressed after surgery and/or systemic chemotherapy and they have no standard-of-care options.…”

Section: Discussionmentioning

confidence: 99%

“…OBI-999 has shown low nanomolar cytotoxicity in tumor cells with high Globo H expression and exhibited a bystander killing effect on tumor cells with minimal Globo H expression. 7 Furthermore, after treatment, OBI-999 and free MMAE gradually accumulated in the tumor but decreased quickly in normal tissues in animal studies. Excellent dose-dependent tumor growth inhibition by OBI-999 was demonstrated in animal models using Globo H–expressing cancer cells.…”

Section: Introductionmentioning

confidence: 95%

“…Excellent dose-dependent tumor growth inhibition by OBI-999 was demonstrated in animal models using Globo H–expressing cancer cells. 7 …”

Section: Introductionmentioning

confidence: 99%

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First-in-Human Study of OBI-999, a Globo H-Targeting Antibody-Drug Conjugate, in Patients With Advanced Solid Tumors

Tsimberidou

Beck

et al. 2023

JCO Precision Oncology

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PURPOSE OBI-999 is a novel antibody-drug conjugate comprising the Globo H–targeting antibody (OBI-888) linked to the cytotoxic payload monomethyl auristatin E. OBI-999 demonstrated excellent dose-dependent tumor growth inhibition in breast, gastric, and pancreatic cancer xenograft models as well as a lung cancer patient–derived xenograft model. We conducted a phase I study of OBI-999 monotherapy in patients with advanced cancer (ClinicalTrials.gov identifier: NCT04084366 ). PATIENTS AND METHODS OBI-999 was administered intravenously at doses of 0.4, 0.8, 1.2, and 1.6 mg/kg every 21 days as part of a 3 + 3 trial design. Primary end points were the incidence of dose-limiting toxicities and adverse events and determination of the maximum tolerated dose (MTD)/recommended phase II dose. RESULTS Fifteen adult patients were treated. OBI-999 was well tolerated up to 1.2 mg/kg, the maximum tolerated dose. The most common treatment-emergent adverse events were neutropenia and anemia. OBI-999 exhibited nonlinear pharmacokinetics at all doses, with lower clearance at higher doses. The three patients treated at the 1.6 mg/kg dose level developed grade 4 neutropenia during cycles 1 and 2. Five (33.3%) patients had stable disease (SD) including one patient with adenoid cystic carcinoma of the oropharynx with SD for 13 cycles and one patient with gastroesophageal junction adenocarcinoma with SD for eight cycles. OBI-999 was well tolerated; however, dose-dependent, noncumulative neutropenia was dose-limiting. CONCLUSION The recommended phase II dose was determined to be 1.2 mg/kg once every 3 weeks. A phase II cohort-expansion study is now enrolling patients with pancreatic, colorectal, and other cancers expressing high levels of Globo H.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

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First-in-Human Study of OBI-999, a Globo H-Targeting Antibody-Drug Conjugate, in Patients With Advanced Solid Tumors

Tsimberidou

Beck

et al. 2023

JCO Precision Oncology

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“…As such, conjugating this antibody with the saporin toxin, these authors developed an immunotoxin able to reduce the viability of breast cancer cells in vitro and in vivo. Furthermore, a novel antibody-drug conjugate (OBI-999), derived from an anti-Globo-H mAb conjugated with a monomethyl auristatin E (MMAE), displays excellent tumor inhibition in different animal models, including breast, gastric, pancreatic, and lung cancers [143]. Further work is needed to validate these novel drugs for the treatment of solid tumors; hence, two phase I/II clinical trials are currently evaluating the safety, pharmacocynetics, and therapeutic activity of the anti-globo H mAb OBI-888 in multiple advanced and metastatic solid tumors (NCT03573544), as well as the immunotoxin OBI-999 in advanced solid tumors (NCT04084366).…”

Section: Globo-seriesmentioning

confidence: 99%

Targeting Tumor Glycans for Cancer Therapy: Successes, Limitations, and Perspectives

Berois

Pittini

Osinaga

2022

Cancers

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Aberrant glycosylation is a hallmark of cancer and can lead to changes that influence tumor behavior. Glycans can serve as a source of novel clinical biomarker developments, providing a set of specific targets for therapeutic intervention. Different mechanisms of aberrant glycosylation lead to the formation of tumor-associated carbohydrate antigens (TACAs) suitable for selective cancer-targeting therapy. The best characterized TACAs are truncated O-glycans (Tn, TF, and sialyl-Tn antigens), gangliosides (GD2, GD3, GM2, GM3, fucosyl-GM1), globo-serie glycans (Globo-H, SSEA-3, SSEA-4), Lewis antigens, and polysialic acid. In this review, we analyze strategies for cancer immunotherapy targeting TACAs, including different antibody developments, the production of vaccines, and the generation of CAR-T cells. Some approaches have been approved for clinical use, such as anti-GD2 antibodies. Moreover, in terms of the antitumor mechanisms against different TACAs, we show results of selected clinical trials, considering the horizons that have opened up as a result of recent developments in technologies used for cancer control.

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“…This assembly technology was applied in the preparation of the ADC OBI-999 ( 60 ), which contains the antibody OBI-888 that targets the tumor-associated carbohydrate antigen globo H (GH). OBI-999 exhibited very suitable pharmacological properties, including efficient internalization rate, tumor-specific ADC accumulation, payload released against GH-expressing cells, a bystander effect, efficacy in animal models, and a safety margin in monkeys [ 116 ] ( Scheme 7 B).…”

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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Preclinical Studies of OBI-999: A Novel Globo H–Targeting Antibody–Drug Conjugate

Cited by 18 publications

References 34 publications

First-in-Human Study of OBI-999, a Globo H-Targeting Antibody-Drug Conjugate, in Patients With Advanced Solid Tumors

First-in-Human Study of OBI-999, a Globo H-Targeting Antibody-Drug Conjugate, in Patients With Advanced Solid Tumors

Targeting Tumor Glycans for Cancer Therapy: Successes, Limitations, and Perspectives

Antibody-Drug Conjugates Containing Payloads from Marine Origin

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