An optimized IgG-based B7-H3xCD3 bispecific antibody for treatment of gastrointestinal cancers

Zekri, Latifa; Lutz, Martina S.; Prakash, Nisha; Manz, Timo; Klimovich, Boris; Mueller, Stefanie; Hoerner, Sebastian von; Hagelstein, Ilona; Engel, Monika; Chashchina, Anna; Pfluegler, Martin; Jung, Gundram; Salih, Helmut R.

doi:10.1016/j.ymthe.2023.02.010

Cited by 15 publications

(18 citation statements)

References 53 publications

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“…In this context it is particularly noteworthy that CC-3 triggered mainly the proliferation of memory T cells, which are considered to be crucial for therapeutic success (19,20). These findings support and extend our recently reported data for CC-3 in CRC (16). Of note, various factors like the tumor microenvironment and T cell exhaustion influence the therapeutic success of bsAb treatment and are not accounted for in our experimental systems.…”

Section: Discussionsupporting

confidence: 92%

“…We have recently reported on the preclinical characterization of an optimized B7-H3xCD3 bsAb and showed that targeting a membrane-proximal B7-H3 epitope allows for reduction of CD3 affinity while maintaining therapeutic efficacy. In analyses with colorectal cancer cells, our lead compound CC-3 demonstrated superior tumor cell killing, T cell activation, proliferation, and memory formation, while undesired cytokine release was reduced (16). Based on these characteristics and the aforementioned data on the expression and pathophysiological involvement of B7-H3 we reasoned that CC-3 would also constitute a promising compound for other gastrointestinal cancer entities.…”

Section: Discussionmentioning

confidence: 92%

“…Flow cytometric analysis revealed substantial B7-H3 expression in all tested cell lines (Figure 1B). Next we studied binding of our B7-H3xCD3 bsAb CC-3, which contains the variable domain of 7C4 cloned into our previously described IgGsc bsAb format (13), with the single chain sequence of UCHT-1 carrying four mutations in the CDR-H2 and one mutation in the FR-H3 resulting in reduced affinity to CD3 (clone M18) as effector part (Figure 1C) (16). Binding titration experiments using the indicated pancreatic, hepatic and gastric cell lines revealed EC 50 values between 4.59 nM and 19.71 nM (Figure 1D), whereas no unspecific binding to B7-H3-negative cells was observed (Figures S1A, B).…”

Section: Characterization Of B7-h3 Expression and Binding Of The B7-h...mentioning

confidence: 99%

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IgG-based B7-H3xCD3 bispecific antibody for treatment of pancreatic, hepatic and gastric cancer

et al. 2023

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T cell-based immunotherapy has significantly improved treatment options for many malignancies. However, despite these and other therapeutic improvements over the last decades, gastrointestinal cancers, in particular pancreatic, hepatic and gastric cancer, are still characterized by high relapse rates and dismal prognosis, with an accordingly high unmet medical need for novel treatment strategies. We here report on the preclinical characterization of a novel bispecific antibody in an IgG-based format termed CC-3 with B7-H3xCD3 specificity. In many cancer entities including pancreatic, hepatic and gastric cancers, B7-H3 (CD276) is overexpressed on tumor cells and also on the tumor vasculature, the latter allowing for improved access of immune effector cells into the tumor site upon therapeutic targeting. We demonstrate that CC-3 induces profound T cell reactivity against various pancreatic, hepatic and gastric cancer cell lines as revealed by analysis of activation, degranulation and secretion of IL2, IFNγ as well as perforin, resulting in potent target cell lysis. Moreover, CC-3 induced efficient T cell proliferation and formation of T cell memory subsets. Together, our results emphasize the potential of CC-3, which is presently being GMP-produced to enable clinical evaluation for treatment of pancreatic, hepatic and gastric cancer.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 92%

Section: Characterization Of B7-h3 Expression and Binding Of The B7-h...mentioning

confidence: 99%

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IgG-based B7-H3xCD3 bispecific antibody for treatment of pancreatic, hepatic and gastric cancer

et al. 2023

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“…B7-H3 has become a focal point for scientific inquiry due to its significant role in various cancer-related processes, encompassing tumour metabolism, angiogenesis, invasion and therapy resistance. 33 While B7-H3 exhibits crucial role in multiple cancer progression. [34][35][36] The dual role of B7-H3 in the immune system has given rise to debates, with some studies suggesting its activity as a co-stimulatory fac-…”

Section: Discussionmentioning

confidence: 99%

NR1D1‐transactivated lncRNA NUTM2A‐AS1 promotes chemoresistance and immune evasion in neuroblastoma via inhibiting B7‐H3 degradation

Xiang,

Li,

Liu

et al. 2024

J Cellular Molecular Medi

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Neuroblastoma (NB), a common solid tumour in young children originating from the sympathetic nervous system during embryonic development, poses challenges despite therapeutic advances like high‐dose chemotherapy and immunotherapy. Some survivors still grapple with severe side effects and drug resistance. The role of lncRNA NUTM2A‐AS1 has been explored in various cancers, but its function in drug‐resistant NB progression is unclear. Our study found that NUTM2A‐AS1 expression in cisplatin‐resistant NB cells increased in a time‐ and dose‐dependent manner. Knockdown of NUTM2A‐AS1 significantly improved NB cell sensitivity to cisplatin and inhibited metastatic abilities. Additionally, we identified B7‐H3, an immune checkpoint‐related protein, as a NUTM2A‐AS1‐associated protein in NB cells. NUTM2A‐AS1 was shown to inhibit the protein degradation of B7‐H3. Moreover, NUTM2A‐AS1 modulated immune evasion in cisplatin‐resistant NB cells through B7‐H3. Furthermore, NUTM2A‐AS1 expression in cisplatin‐resistant NB cells was transactivated by NR1D1. In summary, our results unveil the molecular or biological relationship within the NR1D1/NUTM2A‐AS1/B7‐H3 axis in NB cells under cisplatin treatment, providing an intriguing avenue for fundamental research into cisplatin‐resistant NB.

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“…Knockdown or targeted therapies of B7-H3/HER2 in NCI-N87 cells significantly suppressed cell proliferation, migration, invasion and adhesion in vitro. 96 Studies on colorectal cancer 97,98 suggest that B7-H3 may be a potential therapeutic target for GC. However, the clear effect of anti-B7-H3 treatment on GC or gastric carcinogenesis has not been elucidated.…”

Section: B7-h3mentioning

confidence: 99%

The expression and function of the B7 family in Helicobacter pylori infection and gastric carcinogenesis process

Zhang

Zhao

et al. 2023

Helicobacter

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Gastric cancer (GC) was the fifth most common cancer and the fourth leading cause of cancer-related deaths worldwide in 2020. 1 In 2010-2014, the 5-year-survival was very high in Korea (69%) and Japan (60%), but in China, it was only 35.9%, 2 where initial asymptomatic development and subsequent nonspecific symptoms result in a diagnosis at advanced stages with a poor prognosis. Assuming that the current incidence rates remain the same, the annual number of new GC cases are predicted to increase from 1.09 million cases to 1.77 million cases by 2040. 3 Helicobacter pylori is an important GC risk factor. 4 The Correa model 5 demonstrates the progression of human gastric carcinogenesis from the normal gastric mucosa to cancer. Persistent H. pylori

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An optimized IgG-based B7-H3xCD3 bispecific antibody for treatment of gastrointestinal cancers

Cited by 15 publications

References 53 publications

IgG-based B7-H3xCD3 bispecific antibody for treatment of pancreatic, hepatic and gastric cancer

IgG-based B7-H3xCD3 bispecific antibody for treatment of pancreatic, hepatic and gastric cancer

NR1D1‐transactivated lncRNA NUTM2A‐AS1 promotes chemoresistance and immune evasion in neuroblastoma via inhibiting B7‐H3 degradation

The expression and function of the B7 family in Helicobacter pylori infection and gastric carcinogenesis process

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