P1.01-070 BIW-8962, an Anti-GM2 Ganglioside Monoclonal Antibody, in Advanced/Recurrent Lung Cancer: A Phase I/II Study

Lee, J.; Kim, J.; Kim, S.; Kang, Jin Hyoung; Lee, D.H.; Cho, B.C.; Shiraishi, Norio; Strout, Vincent; Park, K.

doi:10.1016/j.jtho.2017.09.724

Cited by 5 publications

(2 citation statements)

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“…In view of the aberrant expression of certain GSLs in cancer, over the past two decades few antibodies have been evaluated in preclinical studies or clinical investigation. Examples include the mAb hu14.18K322A, which specifically recognizes the ganglioside GD2, evaluated in a phase II trial in neuroblastoma patients [64] and the mAb BIW-8962 against the ganglioside GM2, highly expressed in lung cancer [65]. However, glycans are considered poor immunogens [66,67] and the challenging generation of high affinity antibodies against TACAs poses a limit to immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

A bispecific, crosslinking lectibody activates cytotoxic T cells and induces cancer cell death

et al. 2022

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Background Aberrant glycosylation patterns play a crucial role in the development of cancer cells as they promote tumor growth and aggressiveness. Lectins recognize carbohydrate antigens attached to proteins and lipids on cell surfaces and represent potential tools for application in cancer diagnostics and therapy. Among the emerging cancer therapies, immunotherapy has become a promising treatment modality for various hematological and solid malignancies. Here we present an approach to redirect the immune system into fighting cancer by targeting altered glycans at the surface of malignant cells. We developed a so-called “lectibody”, a bispecific construct composed of a lectin linked to an antibody fragment. This lectibody is inspired by bispecific T cell engager (BiTEs) antibodies that recruit cytotoxic T lymphocytes (CTLs) while simultaneously binding to tumor-associated antigens (TAAs) on cancer cells. The tumor-related glycosphingolipid globotriaosylceramide (Gb3) represents the target of this proof-of-concept study. It is recognized with high selectivity by the B-subunit of the pathogen-derived Shiga toxin, presenting opportunities for clinical development. Methods The lectibody was realized by conjugating an anti-CD3 single-chain antibody fragment to the B-subunit of Shiga toxin to target Gb3+ cancer cells. The reactive non-canonical amino acid azidolysine (AzK) was inserted at predefined single positions in both proteins. The azido groups were functionalized by bioorthogonal conjugation with individual linkers that facilitated selective coupling via an alternative bioorthogonal click chemistry reaction. In vitro cell-based assays were conducted to evaluate the antitumoral activity of the lectibody. CTLs, Burkitt´s lymphoma-derived cells and colorectal adenocarcinoma cell lines were screened in flow cytometry and cytotoxicity assays for activation and lysis, respectively. Results This proof-of-concept study demonstrates that the lectibody activates T cells for their cytotoxic signaling, redirecting CTLs´ cytotoxicity in a highly selective manner and resulting in nearly complete tumor cell lysis—up to 93%—of Gb3+ tumor cells in vitro. Conclusions This research highlights the potential of lectins in targeting certain tumors, with an opportunity for new cancer treatments. When considering a combinatorial strategy, lectin-based platforms of this type offer the possibility to target glycan epitopes on tumor cells and boost the efficacy of current therapies, providing an additional strategy for tumor eradication and improving patient outcomes.

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Section: Introductionmentioning

confidence: 99%

A bispecific, crosslinking lectibody activates cytotoxic T cells and induces cancer cell death

et al. 2022

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“…For example, the antibody hu14.18K322A, which specifically recognize GD2, is being investigated in a phase II trial in neuroblastoma patients ( Furman et al, 2017 ). Another example, the antibody BIW-8962, targets GM2, which is highly expressed in lung cancer ( Lee et al, 2017 ). Racotumomab as an anti-idiotypic antibody vaccine that response against NeuGcGM3 can significantly extend the life of lung cancer patients by inhibiting the growth of their tumors.…”

Section: Summary and Perspectivesmentioning

confidence: 99%

Biological Roles of Aberrantly Expressed Glycosphingolipids and Related Enzymes in Human Cancer Development and Progression

Zhuo

Guan

2018

Front. Physiol.

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Glycosphingolipids (GSLs), which consist of a hydrophobic ceramide backbone and a hydrophilic carbohydrate residue, are an important type of glycolipid expressed in surface membranes of all animal cells. GSLs play essential roles in maintenance of plasma membrane stability, in regulation of numerous cellular processes (including adhesion, proliferation, apoptosis, and recognition), and in modulation of signal transduction pathways. GSLs have traditionally been classified as ganglio-series, lacto-series, or globo-series on the basis of their diverse types of oligosaccharide chains. Structures and functions of specific GSLs are also determined by their oligosaccharide chains. Different cells and tissues show differential expression of GSLs, and changes in structures of GSL glycan moieties occur during development of numerous types of human cancer. Association of GSLs and/or related enzymes with initiation and progression of cancer has been documented in 100s of studies, and many such GSLs are useful markers or targets for cancer diagnosis or therapy. In this review, we summarize (i) recent studies on aberrant expression and distribution of GSLs in common human cancers (breast, lung, colorectal, melanoma, prostate, ovarian, leukemia, renal, bladder, gastric); (ii) biological functions of specific GSLs in these cancers.

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Anti-glycan antibodies: roles in human disease

Temme

Butler

Gildersleeve

2021

Biochemical Journal

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Carbohydrate-binding antibodies play diverse and critical roles in human health. Endogenous carbohydrate-binding antibodies that recognize bacterial, fungal, and other microbial carbohydrates prevent systemic infections and help maintain microbiome homeostasis. Anti-glycan antibodies can have both beneficial and detrimental effects. For example, alloantibodies to ABO blood group carbohydrates can help reduce the spread of some infectious diseases, but they also impose limitations for blood transfusions. Antibodies that recognize self-glycans can contribute to autoimmune diseases, such as Guillain-Barre syndrome. In addition to endogenous antibodies that arise through natural processes, a variety of vaccines induce anti-glycan antibodies as a primary mechanism of protection. Some examples of approved carbohydrate-based vaccines that have had a major impact on human health are against pneumococcus, Haemophilus influeanza type b, and Neisseria meningitidis. Monoclonal antibodies specifically targeting pathogen associated or tumor associated carbohydrate antigens (TACAs) are used clinically for both diagnostic and therapeutic purposes. This review aims to highlight some of the well-studied and critically important applications of anti-carbohydrate antibodies.

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P1.01-070 BIW-8962, an Anti-GM2 Ganglioside Monoclonal Antibody, in Advanced/Recurrent Lung Cancer: A Phase I/II Study

Cited by 5 publications

References 0 publications

A bispecific, crosslinking lectibody activates cytotoxic T cells and induces cancer cell death

A bispecific, crosslinking lectibody activates cytotoxic T cells and induces cancer cell death

Biological Roles of Aberrantly Expressed Glycosphingolipids and Related Enzymes in Human Cancer Development and Progression

Anti-glycan antibodies: roles in human disease

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