Single agent activity of ZW25, a HER2-targeted bispecific antibody, in heavily pretreated HER2-expressing cancers.

Meric‐Bernstam, Funda; Beeram, M.; Mayordomo, J. I.; Hanna, Diana L.; Ajani, Jaffer A.; Murphy, Mariela A. Blum; Murthy, Rashmi Krishna; Piha‐Paul, Sarina A.; Bauer, Todd M.; Bendell, Johanna C.; El-Khoueiry, Anthony B.; Lenz, Heinz‐Josef; Press, Michael F.; Royer, Nels; Hausman, Diana F.; Hamilton, Erika

doi:10.1200/jco.2018.36.15_suppl.2500

Cited by 79 publications

(58 citation statements)

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“…Preclinically, its unique binding facilitates increased tumor cell binding, ZW25-HER2 clustering, and enhanced internalization (including in the setting of lower HER2 concentrations). In a phase I trial, ZW25 led to OR s in heavily pretreated patients with HER2-amplified/overexpressing breast cancer (33% ORR), gastroesophageal cancer (44% ORR), as well as other HER2-amplified/overexpressing tumor types (33% ORR), including colorectal cancer and gallbladder cancer (45). MCLA-128 targets both HER2 and HER3, enhancing antibody-dependent cell-mediated cytotoxicity, with a CBR of 70% in heavily pretreated patients (46).…”

Section: Bispecific Antibodiesmentioning

confidence: 99%

Advances in HER2-Targeted Therapy: Novel Agents and Opportunities Beyond Breast and Gastric Cancer

Meric‐Bernstam

Johnson

Dumbrava

et al. 2019

Clinical Cancer Research

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265

177

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The introduction of HER2-targeted therapy for breast and gastric patients with ERBB2 (HER2) amplification/overexpression has led to dramatic improvements in oncologic outcomes. In the past 20 years, five HER2-targeted therapies have been FDA approved, with four approved in the past 8 years. HER2-targeted therapy similarly was found to improve outcomes in HER2-positive gastric cancer. Over the past decade, with the introduction of next-generation sequencing into clinical practice, our understanding of HER2 biology has dramatically improved. We have recognized that HER2 amplification is not limited to breast and gastric cancer but is also found in a variety of tumor types such as colon cancer, bladder cancer, and biliary cancer. Furthermore, HER2-targeted therapy has signal of activity in several tumor types. In addition to HER2 amplification and overexpression, there is also increased recognition of activating HER2 mutations and their potential therapeutic relevance. Furthermore, there is a rapidly growing number of new therapeutics targeting HER2 including smallmolecule inhibitors, antibody-drug conjugates, and bispecific antibodies. Taken together, an increasing number of patients are likely to benefit from approved and emerging HER2targeted therapies.

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Section: Bispecific Antibodiesmentioning

confidence: 99%

Advances in HER2-Targeted Therapy: Novel Agents and Opportunities Beyond Breast and Gastric Cancer

Meric‐Bernstam

Johnson

Dumbrava

et al. 2019

Clinical Cancer Research

Self Cite

265

177

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“…The preclinical analysis has revealed that ZW25 manifests antitumor activity over a range of HER2 expression levels and inhibits HER2 signaling more potently than either trastuzumab or pertuzumab. In a phase I basket trial, single-agent ZW25 showed encouraging efficacy in heavily pretreated patients with HER2-positive gastroesophageal cancer, with an ORR of 44% and a disease control rate (DCR) of 56% [46]. Toxicities were manageable with almost all adverse events classified as grade 1 or 2.…”

Section: Zw25mentioning

confidence: 99%

Emerging Targeted Therapies for HER2 Positive Gastric Cancer That Can Overcome Trastuzumab Resistance

Mitani

Kawakami

2020

Cancers

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Trastuzumab, a monoclonal antibody to human epidermal growth factor receptor 2 (HER2), has improved survival in patients with HER2-positive advanced gastric or gastroesophageal junction cancer (AGC). The inevitable development of resistance to trastuzumab remains a problem, however, with several treatment strategies that have proven effective in breast cancer having failed to show clinical benefit in AGC. In this review, we summarize the mechanisms underlying resistance to HER2-targeted therapy and outline past and current challenges in the treatment of HER2-positive AGC refractory to trastuzumab. We further describe novel agents such as HER2 antibody-drug conjugates that are under development and have shown promising antitumor activity in early studies. basis of these results, trastuzumab was approved for AGC with a high HER2 expression level, and trastuzumab-containing regimens are now a standard option for the first-line treatment of such patients, who accounted for 7% to 17% of all individuals with gastric cancer [3-5]. Derivatives of the ToGA Regimen in the First-Line SettingThe ToGA trial adopted a regimen of cisplatin combined with either 5-fluorouracil (5-FU) or capecitabine, whereas subsequent prospective studies found similar treatment outcomes with regimens containing oxaliplatin or tegafur-gimeracil-oteracil (S-1). In a single-arm, nonrandomized phase II trial (HER2-based strategy in stomach cancer (HERBIS)-1) performed in Japan [6], trastuzumab in combination with S-1 plus cisplatin yielded a confirmed ORR of 68%, with a median OS and a median PFS of 16.0 and 7.8 months, respectively, in HER2-positive AGC patients with measurable lesions, with these results being similar to those of the ToGA trial [2]. Similar efficacy was also apparent in AGC patients without measurable lesions (HERBIS-1B study) [7]. Three phase II studies that assessed the combination of trastuzumab with capecitabine plus oxaliplatin reported a median OS, a median PFS, and an ORR of 13.8 to 21.0 months, 7.1 to 9.8 months, and 46.7% to 67.3%, respectively [8][9][10]. Trastuzumab in combination with S-1 plus oxaliplatin was also shown to provide a similar treatment outcome in a phase II study, with a median OS, a median PFS, and an ORR of 18.1 months, 8.8 months, and 70.7%, respectively [11]. A meta-analysis of data from these trials revealed that S-1 or oxaliplatin can substitute effectively for capecitabine or 5-FU or for cisplatin, respectively [12].Immune checkpoint inhibitors such as antibodies to programmed cell death-1 (PD-1) have recently revolutionized treatment strategies for advanced cancer. Given that trastuzumab was found to stimulate T cell responses [13], the combination of trastuzumab-containing regimens with antibodies to PD-1 is receiving attention. A phase II study including 37 patients with HER2-positive AGC treated in the first-line setting with capecitabine, oxaliplatin, and trastuzumab in combination with the anti-PD-1 antibody pembrolizumab reported an ORR of 83%, with a median PFS of 11.4 months and a median ...

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“…For monomeric alternative scaffold proteins and fragment antibodies, generation of biparatopic proteins is an extremely efficient way of increasing avidity. Thus, a large number of these proteins have been developed as biparatopic agents [12,[16][17][18][19][20][21][22][23][24][25][26][27][28][29], which is not as important with conventional antibodies because they are already bivalent [5,7,8,10,[30][31][32][33][34][35][36][37].…”

Section: Increased Binding Avidity Of Biparatopic Proteinsmentioning

confidence: 99%

“…Biparatopic antibodies (BpAbs) have been known for almost 30 years [5], but it was not until recently that technological advances [6] allowed the development of biparatopic antibodies with sufficient quality for development into drugs. Currently, two BpAbs against human epidermal growth factor receptor 2 (HER2) are undergoing clinical trial, with one being developed as an antibody-drug conjugate [8,9] and the other being developed as both a naked antibody and an antibody-drug conjugate [10,11]. In addition, one biparatopic DARPin against HER2 is also undergoing clinical trial [12].…”

mentioning

confidence: 99%

Development and activities, including immunocomplex formation, of biparatopic antibodies and alternative scaffold proteins

Akiba

Tsumoto

2020

Translational and Regulatory Sciences

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Biparatopic antibodies and biparatopic alternative scaffolds are proteins that can simultaneously bind two distinct epitopes, and as such are promising formats for the development of next-generation antibody therapeutics. By design, biparatopic proteins have high avidity and can bridge between epitopes in an intra-or intermolecular manner to form diverse immunocomplexes. Some biparatopic proteins can be efficiently internalized into cells, which may be useful for the targeted delivery of therapeutic molecules into cells. In addition, biparatopic proteins can also lock the conformation of membrane proteins to exert an agonist or antagonist effect. Here, we review the development and characteristics of biparatopic proteins and examine how they differ in terms of antigen-binding efficiency, immunocomplex formation and biological activity compared with conventional monoparatopic proteins.

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Single agent activity of ZW25, a HER2-targeted bispecific antibody, in heavily pretreated HER2-expressing cancers.

Cited by 79 publications

References 0 publications

Advances in HER2-Targeted Therapy: Novel Agents and Opportunities Beyond Breast and Gastric Cancer

Advances in HER2-Targeted Therapy: Novel Agents and Opportunities Beyond Breast and Gastric Cancer

Emerging Targeted Therapies for HER2 Positive Gastric Cancer That Can Overcome Trastuzumab Resistance

Development and activities, including immunocomplex formation, of biparatopic antibodies and alternative scaffold proteins

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