Bispecific Antibodies in Cancer Immunotherapy: A Novel Response to an Old Question

Ordóñez-Reyes, Camila; García-Robledo, Juan Esteban; Chamorro, Diego F.; Mosquera, Andrés; Sussmann, Liliana; Ruíz-Patiño, Alejandro; Arrieta, Óscar; Zatarain-Barrón, Lucía; Rojas, Leonardo; Russo, Alessandro; Pérez, Diego; Rolfo, Christian; Cardona, Andrés F.

doi:10.3390/pharmaceutics14061243

Cited by 24 publications

(27 citation statements)

References 88 publications

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“…The standard cancer immunotherapy include mono-specific human antibodies with the two binding sites directed against the same target, but a growing interest in cancer immunotherapy is focusing on immune cell engaging bi-specific antibodies (BsAbs), that are antibody-derivative constructs in which the binding sites are directed to different targets, frequently represented by a TAA for one arm and an immune cell receptor for the other one [ 8 ]. Among them, Catumaxomab, a BsAbs targeting Epithelial cell adhesion molecule (EpCAM) and CD3, was approved by the European Medicines Agency (EMA) in 2009 for the treatment of malignant ascites [ 4 – 6 ] but the presence of rat/mouse hybrid Fc resulted in significant toxicity. At present, 57 BsAbs are in clinical trials for treatment of cancer patients and, in particular, 38 of them exploit the use of T cell-engaging BsAbs [ 7 , 8 ].…”

Section: Discussionmentioning

confidence: 99%

Novel tri-specific tribodies induce strong T cell activation and anti-tumor effects in vitro and in vivo

Passariello

Yoshioka²,

Takahashi³

et al. 2022

J Exp Clin Cancer Res

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Background Immunotherapy based on Bi-specific T Cell Engagers (TCE) represents one of the most attractive strategy to treat cancers resistant to conventional therapies. TCE are antibody-like proteins that simultaneously bind with one arm to a Tumor Associated Antigen (TAA) on cancer cells and with the other one to CD3 complex on a T-cell to form a TCR-independent immune synapse and circumvent Human Leucocyte Antigen restriction. Among them, the tribodies, such as Tb535H, a bi-specific molecule, made up of a Fab and a scFv domain both targeting 5T4 and another scFv targeting CD3, have demonstrated anti-tumor efficacy in preclinical studies. Methods Here, we generated five novel tri-specific and multi-functional tribodies, called 53X tribodies, composed of a 5T4 binding Fab arm and a CD3 binding scFv, but differently from the parental Tb535H, they contain an additional scFv derived from an antibody specific for an immune checkpoint, such as PD-1, PD-L1 or LAG-3. Results Compared with the parental Tb535H bi-specific T cell engager targeting 5T4, the novel 53X tribodies retained similar binding properties of Tb535H tribody, but showed enhanced anti-tumor potency due to the incorporation of the checkpoint inhibitory moiety. In particular, one of them, called 53L10, a tri-specific T cell engager targeting 5T4, CD3 and PD-L1, showed the most promising anti-tumor efficacy in vitro and led to complete tumor regression in vivo. Conclusions The novel tribodies have the potential to become strong and safe therapeutic drugs, allowing to reduce also the cost of production as one single molecule contains three different specificities including the anti-TAA, anti-CD3 and anti-IC binding arms.

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Section: Discussionmentioning

confidence: 99%

Novel tri-specific tribodies induce strong T cell activation and anti-tumor effects in vitro and in vivo

Passariello

Yoshioka²,

Takahashi³

et al. 2022

J Exp Clin Cancer Res

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“…In recent years, bispecific antibodies treatment has been recognized as another promising approach in cancer immunotherapies ( 51 ). Notably, bispecific antibodies targeting both PD-1/PD-L1 and TGF-β named YM101 and M7824 were developed and achieved superior effects against cancers by overcoming the anti-PD1/PD-L1 drug resistance induced by TGF-β ( 52 – 54 ).…”

Section: Advances and Limitations Of Current Cancer Immunotherapiesmentioning

confidence: 99%

Dietary fungi in cancer immunotherapy: From the perspective of gut microbiota

Wei

Song²,

Wang³

et al. 2023

Front. Oncol.

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Immunotherapies are recently emerged as a new strategy in treating various kinds of cancers which are insensitive to standard therapies, while the clinical application of immunotherapy is largely compromised by the low efficiency and serious side effects. Gut microbiota has been shown critical for the development of different cancer types, and the potential of gut microbiota manipulation through direct implantation or antibiotic-based depletion in regulating the overall efficacy of cancer immunotherapies has also been evaluated. However, the role of dietary supplementations, especially fungal products, in gut microbiota regulation and the enhancement of cancer immunotherapy remains elusive. In the present review, we comprehensively illustrated the limitations of current cancer immunotherapies, the biological functions as well as underlying mechanisms of gut microbiota manipulation in regulating cancer immunotherapies, and the benefits of dietary fungal supplementation in promoting cancer immunotherapies through gut microbiota modulation.

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“…In murine models, trispecific antibodies based on ch14.18 or hu3F8 exhibited remarkable control over metastatic neuroblastoma, melanoma, and osteosarcoma tumors ( Xu et al, 2015 ; Park and Cheung, 2020 ; Nakajima et al, 2021 ; Park et al, 2021 ; Zirngibl et al, 2021 ). Encouraged by preclinical success, phase I/II clinical trials employing trispecific antibodies (hu3F8) have been initiated for neuroblastoma, osteosarcoma, and small cell lung cancer ( Hattinger et al, 2019 ; Yankelevich et al, 2019 ; Ordóñez-Reyes et al, 2022 ). Initial results from the neuroblastoma and osteosarcoma trials indicate a 33% clinical response rate among patients with relapsed/refractory disease who completed Phase I ( Yankelevich et al, 2019 ).…”

Section: Gd2 As a Target Antigen For Immunotherapiesmentioning

confidence: 99%

Biology of GD2 ganglioside: implications for cancer immunotherapy

Machy,

Mortier,

Birklé

2023

Front. Pharmacol.

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Part of the broader glycosphingolipid family, gangliosides are composed of a ceramide bound to a sialic acid-containing glycan chain, and locate at the plasma membrane. Gangliosides are produced through sequential steps of glycosylation and sialylation. This diversity of composition is reflected in differences in expression patterns and functions of the various gangliosides. Ganglioside GD2 designates different subspecies following a basic structure containing three carbohydrate residues and two sialic acids. GD2 expression, usually restrained to limited tissues, is frequently altered in various neuroectoderm-derived cancers. While GD2 is of evident interest, its glycolipid nature has rendered research challenging. Physiological GD2 expression has been linked to developmental processes. Passing this stage, varying levels of GD2, physiologically expressed mainly in the central nervous system, affect composition and formation of membrane microdomains involved in surface receptor signaling. Overexpressed in cancer, GD2 has been shown to enhance cell survival and invasion. Furthermore, binding of antibodies leads to immune-independent cell death mechanisms. In addition, GD2 contributes to T-cell dysfunction, and functions as an immune checkpoint. Given the cancer-associated functions, GD2 has been a source of interest for immunotherapy. As a potential biomarker, methods are being developed to quantify GD2 from patients’ samples. In addition, various therapeutic strategies are tested. Based on initial success with antibodies, derivates such as bispecific antibodies and immunocytokines have been developed, engaging patient immune system. Cytotoxic effectors or payloads may be redirected based on anti-GD2 antibodies. Finally, vaccines can be used to mount an immune response in patients. We review here the pertinent biological information on GD2 which may be of use for optimizing current immunotherapeutic strategies.

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Bispecific Antibodies in Cancer Immunotherapy: A Novel Response to an Old Question

Cited by 24 publications

References 88 publications

Novel tri-specific tribodies induce strong T cell activation and anti-tumor effects in vitro and in vivo

Novel tri-specific tribodies induce strong T cell activation and anti-tumor effects in vitro and in vivo

Dietary fungi in cancer immunotherapy: From the perspective of gut microbiota

Biology of GD2 ganglioside: implications for cancer immunotherapy

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