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“Antibodies to Watch in 2025” is now online!

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Read all about Antibodies to Watch in 2025 here.

From the abstract:

The commercial development of antibody therapeutics is a global enterprise involving thousands of biopharmaceutical firms and supporting service organizations. To date, their combined efforts have resulted in over 200 marketed antibody therapeutics and a pipeline of nearly 1,400 investigational product candidates that are undergoing evaluation in clinical studies as treatments for a wide variety of diseases. Here, we discuss key events in antibody therapeutics development that occurred during 2024 and forecast key events related to the late-stage clinical pipeline that may occur in 2025. In particular, we report on 21 antibody therapeutics granted a first approval in at least one country or region during 2024, including bispecific antibodies tarlatamab (IMDELLTRA®), zanidatamab (Ziihera®), zenocutuzumab (BIZENGRI®), odronextamab (Ordspono®), ivonescimab (依達方®), and antibody–drug conjugate (ADC) sacituzumab tirumotecan (佳泰萊®). We also discuss 30 investigational antibody therapeutics for which marketing applications were undergoing review by at least one regulatory agency, as of our last update on December 9, 2024, including ADCs datopotamab deruxtecan, telisotuzumab vedotin, patritumab deruxtecan, trastuzumab botidotin, becotatug vedotin, and trastuzumab rezetecan. Of 178 antibody therapeutics we include in the late-stage pipeline, we summarize key data for 18 for which marketing applications may be submitted by the end of 2025, such as bi- or multispecific antibodies denecimig, sonelokimab, erfonrilimab, and anbenitamab. Key trends in the development and approval of antibody formats such as bispecifics and ADCs, as well as clinical-phase transition and global approval success rates for these antibody formats, are reported.

“Antibodies to Watch” is an article series started in 2010. All articles are published in mAbs. The series Collection can be accessed here.

 

FDA approves zanidatamab (Ziihera®)

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On November 20, 2024, Jazz Pharmaceuticals announced that FDA granted accelerated approval of Ziihera® (zanidatamab-hrii) 50mg/mL for injection for intravenous use for the treatment of adults with previously treated, unresectable or metastatic HER2-positive (IHC 3+) biliary tract cancer (BTC), as detected by an FDA-approved test.[28] A confirmatory, randomized Phase 3 trial (HERIZON-BTC-302; NCT06282575) evaluating zanidatamab in combination with standard-of-care therapy versus standard-of-care therapy alone in the first-line setting for patients with HER2-positive BTC initiated in July 2024 is currently recruiting patients.

Zanidatamab (ZW25) is a humanized, biparatopic, bispecific IgG assembled from half-antibodies (Fab-h-CH2-CH3 x scFv-h-CH2-CH3) that targets two non-overlapping epitopes of HER2. In 2022, Zymeworks licensed the development and commercialization rights across all indications in the United States, Europe, Japan and all other territories, except for those Asia/Pacific territories previously licensed by Zymeworks, to Jazz Pharmaceuticals. BeiGene acquired exclusive development and commercial rights to zanidatamab, in Asia (excluding Japan), Australia, and New Zealand in 2018. FDA granted Breakthrough Therapy designation for zanidatamab in patients with previously treated HER2 gene-amplified BTC, Fast Track designation for zanidatamab as a single agent for refractory BTC, and Orphan Drug designation for zanidatamab in refractory BTC.

The approval was based in part on the results of the single-arm, Phase 2b trial (HERIZON-BTC-01; NCT04466891) of zanidatamab in patients with HER2-amplified, unresectable, locally advanced, or metastatic BTC with disease progression on previous gemcitabine-based therapy. The efficacy of zanidatamab was evaluated in 62 patients with HER2-positive (IHC 3+ by central assessment) BTC in Cohort 1 of HERIZON-BTC-01, with major efficacy outcome measures of  objective response rate (ORR) and duration of response (DOR) as determined by independent central review according to RECIST (Response Evaluation Criteria in Solid Tumors) v1.1. The study demonstrated an ORR of 52% [95% confidence interval (CI): 39, 65)] with a Kaplan Meier estimated median DOR of 14.9 months [95% CI: 7.4-not estimable] by independent central review [1].

Marketing applications for zanidatamab as a treatment for BTC were also submitted in the European Union and China. Beigene anticipates approval by NMPA for zanidatamab as second-line treatment of HER2+ BTC in the second half of 2025.

[1] ZIIHERA (zanidatamab-hrii) Prescribing Information. Palo Alto, CA: Jazz Pharmaceuticals, Inc.

FDA approves Vyloy (zolbetuximab-clzb)

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On October 18, 2024, the US Food and Drug Administration (FDA) approved zolbetuximab-clzb (Vyloy, Astellas Pharma US, Inc.) for the first-line treatment of adults with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction (G/GEJ) adenocarcinoma whose tumors are CLDN18.2 positive, as determined by an FDA-approved test. FDA also approved the VENTANA CLDN18 (43-14A) RxDx Assay (Ventana Medical Systems, Inc./Roche Diagnostics) as a companion diagnostic device to identify patients with gastric or GEJ adenocarcinoma who may be eligible for treatment with zolbetuximab.

The recommended zolbetuximab-clzb dosage with fluoropyrimidine- and platinum-containing chemotherapy is 800 mg/m2 intravenously (IV) as the first dose, with subsequent dosages of 600 mg/m2 IV every 3 weeks, or 400 mg/m2 IV every 2 weeks.

Zolbetuximab is a chimeric IgG1 antibody targeting Claudin 18.2 (CLDN18.2) originally developed by Ganymed Pharmaceuticals AG, which was acquired by Astellas. Japan’s Ministry of Health, Labour and Welfare approved VYLOY™ for patients with CLDN18.2-positive, unresectable, advanced or recurrent gastric cancer in March 2024 and zolbetuximab was subsequently approved for untreated CLDN18.2-positive, HER2-negative unresectable advanced G/GEJ adenocarcinoma in the United Kingdom and the European Union in August and September 2024, respectively.

The marketing approvals were based on data from the Phase 3 SPOTLIGHT (NCT03504397) and GLOW clinical trials (NCT03653507). Both were randomized (1:1), double-blind, multicenter trials that included patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic G/GEJ adenocarcinoma. The SPOTLIGHT trial included 565 patients randomized to receive either zolbetuximab (800 mg/m2 loading dose administered IV followed by 600 mg/m2 every 3 weeks) plus mFOLFOX6 chemotherapy (283 patients) or placebo plus mFOLFOX6 (282 patients). The GLOW study evaluated zolbetuximab plus capecitabine and oxaliplatin as first-line treatment in 507 patients.

In the SPOTLIGHT study, the median progression-free survival (PFS) was 10.6 months (95% CI: 8.9, 12.5) in the zolbetuximab-clzb/chemotherapy arm and 8.7 months (95% CI: 8.2, 10.3) in the placebo/chemotherapy arm (hazard ratio [HR] 0.751 [95% CI: 0.598, 0.942]; 1-sided p-value=0.0066). Median overall survival (OS) was 18.2 months (95% CI: 16.4, 22.9) and 15.5 months (95% CI: 13.5, 16.5), respectively, (HR 0.750 [95% CI: 0.601, 0.936]; 1-sided p-value=0.0053).

In the GLOW study, the median PFS was 8.2 months (95% CI: 7.5, 8.8) in the zolbetuximab-clzb/chemotherapy arm and 6.8 months (95% CI: 6.1, 8.1) in the placebo/chemotherapy arm (hazard ratio [HR] 0.687 [95% CI: 0.544, 0.866]; 1-sided p-value=0.0007). Median OS was 14.4 months (95% CI: 12.3, 16.5) and 12.2 months (95% CI: 10.3, 13.7), respectively (HR 0.771 [95% CI: 0.615, 0.965]; 1-sided p-value=0.0118).

Curious about what other antibody therapeutics are approved or in regulatory review? Our online table contains details for over 200 such antibodies! 

TEVIMBRA (tislelizumab-jsgr) granted first FDA approval for esophageal squamous cell carcinoma

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On March 13, 2024, the U.S. Food and Drug Administration (FDA) approved TEVIMBRA (tislelizumab-jsgr) as monotherapy for the treatment of adult patients with unresectable or metastatic esophageal squamous cell carcinoma (ESCC) after prior systemic chemotherapy that did not include a PD-(L)1 inhibitor. TEVIMBRA, a humanized IgG4 antibody engineered with modifications that stabilize the hinge region and abrogate binding to Fc receptors, was approved as an orphan drug for this indication.

FDA’s approval is based on the Phase 3 RATIONALE 302 trial (NCT03430843), which met its primary endpoint in the intention-to-treat (ITT) population, with a median overall survival (OS) in the TEVIMBRA arm or 8.6 months (95% CI: 7.5, 10.4) compared to 6.3 months (95% CI: 5.3, 7.0) in the chemotherapy arm (p=0.0001; hazard ratio [HR]=0.70 [95% CI: 0.57, 0.85]). The results showed a statistically significant and clinically meaningful survival benefit for TEVIMBRA compared with chemotherapy and the safety profile of TEVIMBRA was favorable over chemotherapy.

In 2019, China’s National Medical Products Administration granted the first global approval of tislelizumab. In 2023, the product received approval by the European Commission for advanced or metastatic ESCC after prior chemotherapy, and it received a positive opinion by the Committee for Medicinal Products for Human Use of the European Medicines Agency in February 2024 as a treatment for non-small cell lung cancer across three indications.

Biologics license applications for tislelizumab as first-line treatment for patients with unresectable, recurrent, locally advanced, or metastatic ESCC and patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma are currently undergoing FDA review. The target action dates for these applications are in July and December 2024, respectively.

Details for all approved antibody therapeutics and those in regulatory review can be found in our searchable table.

Crovalimab approved in China

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On February 8, 2024, Chugai Pharmaceutical Co., Ltd. announced that crovalimab (Chinese product name : 派圣凯®) was approved in the People’s Republic of China for treatment of adults and adolescents with paroxysmal nocturnal hemoglobinuria (PNH) not been previously treated with complement inhibitors. The regulatory application was filed by a China affiliate of F. Hoffmann-La Roche Ltd. because Roche is responsible for the development of crovalimab outside Japan and Taiwan. China is the first country in the world to approve crovalimab. Marketing applications for crovalimab have been submitted to regulatory agencies in the US, EU, and Japan.

Crovalimab (SKY59, RG6107, RO7112689) is a complement C5 inhibiting, humanized IgG1k antibody without effector functions that was engineered (M428L/N434A) to have enhanced affinity to FcRn at an acidic pH to extend its plasma half-life. Based on Chugai’s Recycling Antibody® technology, crovalimab is engineered to bind its antigen repeatedly, enabling sustained complement inhibition at a low dose administered subcutaneously (SC) every 4 weeks. Moreover, crovalimab binds a different epitope of C5 compared to existing antibody drugs, suggesting that it represents an alternative option for patients with PNH with a specific C5 gene mutation.

Crovalimab was granted Breakthrough Therapy for PNH by NMPA and the marketing application for crovalimab, which included data from the China-specific Phase 3 COMMODORE 3 study (NCT04654468), was accepted by NMPA under Priority Review.

COMMODORE 3 was a multicenter single-arm trial studying crovalimab in C5 inhibitor-naive patients with PNH in China. Patients (n=51) received crovalimab according to a weight-based dosing schedule, including loading (intravenous (IV) dose on Days 1 and 4, weekly SC doses starting from Day 2) and SC maintenance doses (every 4 weeks starting from Week 5); treatment continued after 24 weeks in patients with clinical benefit. The co-primary efficacy endpoints of hemolysis control and transfusion avoidance (TA) were met. The mean proportion of participants with hemolysis control from Week 5 through to Week 25 was 78.7% (95% CI: 67.8%, 86.6%).1 The difference between the proportion of participants with TA within 24 weeks prior to screening (0.0%) and the proportion of participants with TA from baseline through to Week 25 (51.0%) was statistically significant (p<0.0001). [1]

The global Phase 3 COMMODORE 1 (NCT04432584) and 2 (NCT04434092) studies assessed the efficacy and safety of crovalimab versus eculizumab in participants with PNH that are C5 inhibitor-experienced patients or not previously treated with complement inhibitors, respectively. COMMODORE 1 assessed safety, pharmacokinetics, pharmacodynamics, and exploratory efficacy of crovalimab. Data from the study support the favorable benefit–risk profile of crovalimab, including allowing for SC administration with the option to self-administer. [2] Data from the COMMODORE 2 study presented at European Hematology Association meeting in June 2023 in Frankfurt, Germany demonstrated that SC crovalimab Q4W was non-inferior in disease control to IV eculizumab Q2W with comparable safety for patients who have not been treated with C5 inhibitors. [3]

  1. Liu H, Xia L, Weng J, Zhang F, He C, Gao S, Jia J, Chang AC, Lundberg P, Camelia S. Sima CS, et al. Results from the first Phase 3 crovalimab (c5-inhibitor) study (commodore 3): efficacy and safety in complement inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria (PNH). Presentation at: ASH Annual Meeting and Exposition; New Orleans, 2022 Dec 10-13; Abstract #293. doi.org/10.1182/blood-2022-162452.
  2. Scheinberg P, Cle D, Edwards J, Giai V, Hus M, Kim JS, Barrenetxea Lekue C, Nagy Z, Nur E, Panse J, et al. Phase III randomized, multicenter, open-label COMMODORE 1 trial: comparison of crovalimab vs eculizumab in complement inhibitor-experienced patients with paroxysmal nocturnal hemoglobinuria (PNH). Hemasphere. 2023; 7(Suppl ): e45540d8. 2023 Aug 8. doi: 10.1097/01.HS9.0000967644.45540.d8
  3. Röth A, He G, Brodsky A, Chai-Adisaksopha CC, Dumagay T, Demichelis R, Höglund M, Kelly R, Lee J-H, Nishimura J-I, et al. The PHASE III, randomized COMMODORE 2 trial: results from a multicenter study of crovalimab vs eculizumab in paroxysmal nocturnal hemoglobinuria (PNH) patients naive to complement inhibitors. Hemasphere. 2023; 7(Suppl ): e72750f1.