Bi-specific T-cell engager

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Structure of a BiTE. VH: Heavy chain variable regions. VL: Light chain variable regions. Different specificity is marked with different colours and shapes. The arrows point from N- to C-terminus. Bi-specific T-cell engager.svg
Structure of a BiTE. VH: Heavy chain variable regions. VL: Light chain variable regions. Different specificity is marked with different colours and shapes. The arrows point from N- to C-terminus.

Bi-specific T-cell engager (BiTE) is a class of artificial bispecific monoclonal antibodies that are investigated for use as anti-cancer drugs. They direct a host's immune system, more specifically the T cells' cytotoxic activity, against cancer cells. BiTE is a registered trademark of Micromet AG (fully owned subsidiary of Amgen Inc). [1]

Contents

BiTE molecules are fusion proteins consisting of two single-chain variable fragments (scFvs) of different antibodies, or amino acid sequences from four different genes, on a single peptide chain of about 55 kilodaltons. One of the scFvs binds to T cells via the CD3 receptor, and the other to a tumor cell via a tumor specific molecule. [2] [3]

Mechanism of action

A BiTE linking a T cell to a tumor cell. BiTE antibody en.svg
A BiTE linking a T cell to a tumor cell.

Like other bispecific antibodies, and unlike ordinary monoclonal antibodies, BiTEs form a link between T cells and tumor cells. This causes T cells to exert cytotoxic activity on tumor cells by producing proteins like perforin and granzymes, independently of the presence of MHC I or co-stimulatory molecules. These proteins enter tumor cells and initiate the cell's apoptosis. [2] [4]

This action mimics physiological processes observed during T cell attacks against tumor cells. [4]

BiTEs in clinical assessment or with clinical approvals

Several BiTEs are currently in preclinical and clinical trials to assess their therapeutic efficacy and safety. [5]

Blinatumomab

Blinatumomab links T cells with CD19 receptors found on the surface of B cells. The Food and Drug Administration (US) and the European Medicines Agency approved this therapy for adults with Philadelphia chromosome-negative relapsed or refractory acute lymphoblastic leukemia. [6]

Glofitamab

It is a bispecific CD20-directed CD3 T-cell engager. It was approved for medical use in Canada in March 2023, in the United States in June 2023, and in the European Union in July 2023.

Mosunetuzumab

Bispecifically binds CD20 and CD3 to engage T-cells. Mosunetuzumab was approved for medical use in the European Union in June 2022.

Solitomab

Solitomab links T cells with the EpCAM antigen which is expressed by colon, gastric, prostate, ovarian, lung, and pancreatic cancers. [7] [8]

Talquetamab

This section is an excerpt from Talquetamab.[ edit ]

Talquetamab, sold under the brand name Talvey, is a humanized monoclonal antibody used for the treatment of multiple myeloma. [9] [10] It is a bispecific GPRC5D-directed CD3 T-cell engager. [9] Talquetamab is a bispecific antibody against two targets: human CD3, a T-cell surface antigen, and human G-protein coupled receptor family C group 5 member D (GPRC5D), a tumor-associated antigen with potential antineoplastic activity. [11] Talquetamab binds both targets, drawing the T cells close to the tumor cells, causing a cytotoxic T-lymphocyte response. [11] It is being developed by Janssen Pharmaceuticals. [12]

The most common adverse reactions include cytokine release syndrome, dysgeusia, nail disorder, musculoskeletal pain, skin disorder, rash, fatigue, decreased weight, dry mouth, pyrexia, xerosis, dysphagia, upper respiratory tract infection, and diarrhea. [13]

Talquetamab was approved for medical use in both the United States [9] [13] [14] and the European Union [15] in August 2023. The US Food and Drug Administration (FDA) considers it to be a first-in-class medication. [16]

Tarlatamab

This section is an excerpt from Tarlatamab.[ edit ]

Tarlatamab, sold under the brand name Imdelltra, is an anti-cancer medication used for the treatment of extensive-stage small cell lung cancer. [17] It is a bispecific T-cell engager that binds delta-like ligand 3 and CD3. [17]

The most common adverse reactions include cytokine release syndrome, fatigue, pyrexia, dysgeusia, decreased appetite, musculoskeletal pain, and constipation, anemia and nausea. [18]

It was approved for medical use in the United States in May 2024. [18] [19]

Tebentafusp

After clinical trials, in January 2022, the US FDA approved tebentafusp (a BiTE targeting the gp100 peptide) for HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma. [20]

Epcoritamab

Epcoritamab, sold under the brand name Epkinly, is used for the treatment of diffuse large B-cell lymphoma. Epcoritamab is a bispecific CD20-directed CD3 T-cell engager.

Epcoritamab was approved for medical use in the United States in May 2023, [21] [22] [23] [24] [25] in the European Union in September 2023, and in Canada in December 2023.

Further research

Utilizing the same technology, melanoma (with MCSP specific BiTEs) and acute myeloid leukemia (with CD33 specific BiTEs) can be targeted. [26] As of 2008, research in this area is active. [26]

Another avenue for novel anti-cancer therapies is re-engineering some of the currently used conventional antibodies like trastuzumab (targeting HER2/neu), cetuximab and panitumumab (both targeting the EGF receptor), using the BiTE approach. [27]

As of 2009, BiTEs against CD66e and EphA2 are being developed as well. [28]

Related Research Articles

In biology, chimeric antigen receptors (CARs)—also known as chimeric immunoreceptors, chimeric T cell receptors or artificial T cell receptors—are receptor proteins that have been engineered to give T cells the new ability to target a specific antigen. The receptors are chimeric in that they combine both antigen-binding and T cell activating functions into a single receptor.

<span class="mw-page-title-main">Cancer immunotherapy</span> Artificial stimulation of the immune system to treat cancer

Cancer immunotherapy (immuno-oncotherapy) is the stimulation of the immune system to treat cancer, improving the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology (immuno-oncology) and a growing subspecialty of oncology.

<span class="mw-page-title-main">Ibritumomab tiuxetan</span> Radioimmunotherapy treatment

Ibritumomab tiuxetan, sold under the trade name Zevalin, is a monoclonal antibody radioimmunotherapy treatment for non-Hodgkin's lymphoma. The drug uses the monoclonal mouse IgG1 antibody ibritumomab in conjunction with the chelator tiuxetan, to which a radioactive isotope is added. Tiuxetan is a modified version of DTPA whose carbon backbone contains an isothiocyanatobenzyl and a methyl group.

Tositumomab is a murine monoclonal antibody which targets the CD20 antigen produced in mammalian cell. It was combined with iodine-131 to produce a radiopharmaceutical for unsealed source radiotherapy, Iodine-131 Tositumomab, for the treatment of non-Hodgkins lymphoma. It is classified as a IgG2a lambda antibody.

A bispecific monoclonal antibody is an artificial protein that can simultaneously bind to two different types of antigen or two different epitopes on the same antigen. Naturally occurring antibodies typically only target one antigen. BsAbs can be manufactured in several structural formats. BsAbs can be designed to recruit and activate immune cells, to interfere with receptor signaling and inactivate signaling ligands, and to force association of protein complexes. BsAbs have been explored for cancer immunotherapy, drug delivery, and Alzheimer's disease.

Genmab A/S is a Danish biotechnology company, founded in February 1999 by Florian Schönharting, at the time managing director of BankInvest Biomedical venture fund. The company is based in Copenhagen, Denmark – internationally, it operates through the subsidiaries Genmab B.V. in Utrecht, The Netherlands, Genmab U.S., Inc. in Princeton, USA, and Genmab K.K. in Tokyo, Japan. Genmab is a dual-listed company with shares traded on both the Copenhagen Stock Exchange in Denmark and the NASDAQ Global Select Market in the US.

Blinatumomab, sold under the brand name Blincyto, and known informally as blina, is a biopharmaceutical medication used as a second-line treatment for Philadelphia chromosome-negative relapsed or refractory acute lymphoblastic leukemia. It belongs to a class of constructed monoclonal antibodies, bi-specific T-cell engagers (BiTEs), that exert action selectively and direct the human immune system to act against tumor cells. Blinatumomab specifically targets the CD19 antigen present on B cells. In December 2014, it was approved by the US Food and Drug Administration under the accelerated approval program; marketing authorization depended on the outcome of clinical trials that were ongoing at the time of approval. Blinatumomab is given via intravenous infusion.

Brentuximab vedotin, sold under the brand name Adcetris, is an antibody-drug conjugate medication used to treat relapsed or refractory Hodgkin lymphoma (HL) and systemic anaplastic large cell lymphoma (ALCL), a type of T cell non-Hodgkin lymphoma. It selectively targets tumor cells expressing the CD30 antigen, a defining marker of Hodgkin lymphoma and ALCL. The drug is being jointly marketed by Millennium Pharmaceuticals outside the US and by Seagen in the US.

<span class="mw-page-title-main">Trifunctional antibody</span> Monoclonal antibody

A trifunctional antibody is a monoclonal antibody with binding sites for two different antigens, typically CD3 and a tumor antigen, making it a type of bispecific monoclonal antibody. In addition, its intact Fc-part can bind to an Fc receptor on accessory cells like conventional monospecific antibodies. The net effect is that this type of drug links T cells and monocytes/macrophages, natural killer cells, dendritic cells or other Fc receptor expressing cells to the tumor cells, leading to their destruction.

Patrick Baeuerle is a German-based molecular biologist, immunologist, professor and a biopharmaceutical entrepreneur. Baeuerle is known for his work on tyrosine sulfation of proteins, transcription factor NF-kappaB, and the development of bispecific T-cell engaging antibodies for therapy of cancer.

<span class="mw-page-title-main">Loncastuximab tesirine</span> Medication

Loncastuximab tesirine, sold under the brand name Zynlonta, is a monoclonal antibody conjugate medication used to treat large B-cell lymphoma and high-grade B-cell lymphoma. It is an antibody-drug conjugate (ADC) composed of a humanized antibody targeting the protein CD19.

<span class="mw-page-title-main">Selinexor</span> Anti-cancer drug

Selinexor sold under the brand name Xpovio among others, is a selective inhibitor of nuclear export used as an anti-cancer medication. It works by blocking the action of exportin 1 and thus blocking the transport of several proteins involved in cancer-cell growth from the cell nucleus to the cytoplasm, which ultimately arrests the cell cycle and leads to apoptosis. It is the first drug with this mechanism of action.

Brexucabtagene autoleucel, sold under the brand name Tecartus, is a cell-based gene therapy medication for the treatment of mantle cell lymphoma (MCL) and acute lymphoblastic leukemia (ALL).

Mosunetuzumab, sold under the brand name Lunsumio, is a monoclonal antibody used for the treatment of follicular lymphoma. It bispecifically binds CD20 and CD3 to engage T-cells. It was developed by Genentech.

Teclistamab, sold under the brand name Tecvayli, is a human bispecific monoclonal antibody used for the treatment of relapsed and refractory multiple myeloma. It is a bispecific antibody that targets the CD3 receptor expressed on the surface of T-cells and B-cell maturation antigen (BCMA), which is expressed on the surface of malignant multiple myeloma B-lineage cells.

Talquetamab, sold under the brand name Talvey, is a humanized monoclonal antibody used for the treatment of multiple myeloma. It is a bispecific GPRC5D-directed CD3 T-cell engager. Talquetamab is a bispecific antibody against two targets: human CD3, a T-cell surface antigen, and human G-protein coupled receptor family C group 5 member D (GPRC5D), a tumor-associated antigen with potential antineoplastic activity. Talquetamab binds both targets, drawing the T cells close to the tumor cells, causing a cytotoxic T-lymphocyte response. It is being developed by Janssen Pharmaceuticals.

Glofitamab, sold under the brand name Columvi, is a bispecific monoclonal antibody used for the treatment of large B-cell lymphoma. It is a bispecific CD20-directed CD3 T-cell engager developed by Roche.

Epcoritamab, sold under the brand name Epkinly, is a monoclonal antibody anticancer medication used for the treatment of diffuse large B-cell lymphoma. Epcoritamab is a bispecific CD20-directed CD3 T-cell engager. Epcoritamab was co-developed by AbbVie and Genmab.

Elranatamab, sold under the brand name Elrexfio, is a medication used for the treatment of multiple myeloma. Elranatamab is a bispecific B-cell maturation antigen (BCMA)-directed CD3 T-cell engager. Elranatamab is given by subcutaneous injection.

Tarlatamab, sold under the brand name Imdelltra, is an anti-cancer medication used for the treatment of extensive-stage small cell lung cancer. It is a bispecific T-cell engager that binds delta-like ligand 3 and CD3.

References

  1. ↑ "US Trademark registration no. 3,068,856, serial number 78/040,636". US Patent and Trademark Office.
  2. 1 2 Helwick, Caroline (1 June 2008). "Novel BiTE antibody mediates contact between T cells and cancer cells". Oncology NEWS International. 17 (6). Archived from the original on 16 February 2012. Retrieved 15 August 2008.
  3. ↑ Rüttinger, D.; Zugmaier, G.; Nagorsen, D.; Reinhardt, C.; Baeuerle, P. A. (2008). "BiTE-Antikörper: Durch Bispezifität T-Lymphozyten gegen Tumorzellen richten" [BiTE antibodies: Directing T lymphocytes against tumor cells by bispecifity]. Journal Onkologie (in German) (4).
  4. 1 2 "BiTE Antibody Platform". Micromet Inc.
  5. ↑ Voynov, V; Adam, PJ (2020). "Discovery Strategies to Maximize the Clinical Potential of T-Cell Engaging Antibodies for the Treatment of Solid Tumors". Antibodies. 9 (4): E65–E81. doi: 10.3390/antib9040065 . PMC   7709135 . PMID   33217946. S2CID   227100306.
  6. ↑ Malard, Florent; Mohty, Mohamad (4 April 2020). "Acute lymphoblastic leukaemia". The Lancet. 395 (10230): 1146–1162. doi: 10.1016/s0140-6736(19)33018-1 . ISSN   0140-6736. PMID   32247396. S2CID   214779717.
  7. ↑ Amann, M.; d'Argouges, S.; Lorenczewski, G.; Brischwein, K.; Kischel, R.; Lutterbuese, R.; Mangold, S.; Rau, D.; Volkland, J.; Pflanz, S.; Raum, T.; Münz, M.; Kufer, P.; Schlereth, B.; Baeuerle, P. A.; Friedrich, M. (2009). "Antitumor Activity of an EpCAM/CD3-bispecific BiTE Antibody During Long-term Treatment of Mice in the Absence of T-cell Anergy and Sustained Cytokine Release". Journal of Immunotherapy. 32 (5): 452–464. doi:10.1097/CJI.0b013e3181a1c097. PMID   19609237. S2CID   25568468.
  8. ↑ Kebenko, Maxim; Goebeler, Marie-Elisabeth; Wolf, Martin; Hasenburg, Annette; Seggewiss-Bernhardt, Ruth; Ritter, Barbara; Rautenberg, Beate; Atanackovic, Djordje; Kratzer, Andrea; Rottman, James B.; Friedrich, Matthias (2018). "A multicenter phase 1 study of solitomab (MT110, AMG 110), a bispecific EpCAM/CD3 T-cell engager (BiTE®) antibody construct, in patients with refractory solid tumors". Oncoimmunology. 7 (8): e1450710. doi:10.1080/2162402X.2018.1450710. ISSN   2162-4011. PMC   6136859 . PMID   30221040.
  9. 1 2 3 "Talvey- talquetamab injection". DailyMed. U.S. National Library of Medicine. 18 August 2023. Archived from the original on 24 August 2023. Retrieved 23 August 2023.
  10. ↑ "Talvey EPAR". European Medicines Agency. 21 September 2023. Retrieved 6 October 2023.
  11. 1 2 "Talquetamab". NCI Drug Dictionary. National Cancer Institute. Archived from the original on 11 August 2023. Retrieved 30 January 2023.
  12. ↑ Chari A, Minnema MC, Berdeja JG, Oriol A, van de Donk NW, Rodríguez-Otero P, Askari E, Mateos MV, Costa LJ, Caers J, Verona R, Girgis S, Yang S, Goldsmith RB, Yao X, Pillarisetti K, Hilder BW, Russell J, Goldberg JD, Krishnan A (December 2022). "Talquetamab, a T-Cell-Redirecting GPRC5D Bispecific Antibody for Multiple Myeloma". The New England Journal of Medicine. 387 (24): 2232–2244. doi: 10.1056/NEJMoa2204591 . PMID   36507686. S2CID   254560960.
  13. 1 2 "FDA grants accelerated approval to talquetamab-tgvs for relapsed or refractory multiple myeloma". U.S. Food and Drug Administration (FDA). 9 August 2023. Archived from the original on 11 August 2023. Retrieved 10 August 2023.PD-icon.svg This article incorporates text from this source, which is in the public domain.
  14. ↑ Theoret MR (2023). "Talvey (talquetamab-tgvs) injection" (PDF). Approval Letter. U.S. Food and Drug Administration. Archived from the original (PDF) on 11 August 2023.PD-icon.svg This article incorporates text from this source, which is in the public domain.
  15. ↑ "Talvey Product information". Union Register of medicinal products. 22 August 2023. Archived from the original on 25 August 2023. Retrieved 25 August 2023.
  16. ↑ New Drug Therapy Approvals 2023 (PDF). U.S. Food and Drug Administration (FDA) (Report). January 2024. Archived from the original on 10 January 2024. Retrieved 9 January 2024.
  17. 1 2 "Imdelltra (AMG757)- tarlatamab-dlle kit". DailyMed. 16 May 2024. Retrieved 31 May 2024.
  18. 1 2 "FDA grants accelerated approval to tarlatamab-dlle for extensive stage small cell lung cancer". U.S. Food and Drug Administration (FDA). 16 May 2024. Retrieved 17 May 2024.PD-icon.svg This article incorporates text from this source, which is in the public domain.
  19. ↑ "FDA approves Imdelltra (tarlatamab-dlle), the first and only T-cell engager therapy for the treatment of extensive-stage small cell lung cancer" (Press release). Amgen. 16 May 2024. Retrieved 18 May 2024– via PR Newswire.
  20. ↑ Research, Center for Drug Evaluation and (26 January 2022). "FDA approves tebentafusp-tebn for unresectable or metastatic uveal melanoma". FDA.
  21. ↑ "FDA grants accelerated approval to epcoritamab-bysp for relapsed or refractory diffuse large B-cell lymphoma and high-grade B-cell lymphoma". U.S. Food and Drug Administration (FDA). 19 May 2023. Archived from the original on 23 May 2023. Retrieved 24 May 2023.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  22. ↑ "FDA approves treatment for relapsed or refractory diffuse large B-cell lymphoma and high-grade B-cell lymphoma". U.S. Food and Drug Administration (FDA). 19 May 2023. Archived from the original on 2 June 2023. Retrieved 2 June 2023.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  23. ↑ "Epkinly (epcoritamab-bysp) Approved by U.S. FDA as the First and Only Bispecific Antibody to Treat Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL)" (Press release). AbbVie. 19 May 2023. Archived from the original on 19 May 2023. Retrieved 20 May 2023– via PR Newswire.
  24. ↑ "Drug Approval Package: Epkinly". U.S. Food and Drug Administration (FDA). 26 May 2023. Retrieved 30 May 2023.
  25. ↑ Frampton JE (September 2023). "Epcoritamab: First Approval". Drugs. 83 (14): 1331–1340. doi:10.1007/s40265-023-01930-4. PMID   37597091. S2CID   261030074.
  26. 1 2 Kischel, R; et al. (2008). "Characterization in primates of MCSP- and CD33-specific human BiTE antibodies for treatment of Melanoma and AML" (PDF). Proc Am Assoc Cancer Res. 99. Abs 2404. Archived from the original (PDF) on 19 July 2011.
  27. ↑ Lutterbuese, R; et al. (2008). "Conversion of cetuximab, panitumumab, trastuzumab and omalizumab into T-cell-engaging BiTE antibodies creates novel drug candidates of high potency" (PDF). Proc Am Assoc Cancer Res. 99. Abs 2402. Archived from the original (PDF) on 19 July 2011.
  28. ↑ Baeuerle, PA; Reinhardt, C (2009). "Bispecific T-cell engaging antibodies for cancer therapy". Cancer Research. 69 (12): 4941–4. doi:10.1158/0008-5472.CAN-09-0547. PMID   19509221.

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