Article
Oncology
Lisa A. King, Elisa C. Toffoli, Myrthe Veth, Victoria Iglesias-Guimarais, Manon C. Slot, Derk Amsen, Rieneke van de Ven, Sarah Derks, Marieke F. Fransen, Jurriaan B. Tuynman, Thilo Riedl, Rob C. Roovers, Anton E. P. Adang, Jurjen M. Ruben, Paul W. H. I. Parren, Tanja D. de Gruijl, Hans J. van der Vliet
Summary: This study assessed the antitumor activity and safety of a bispecific antibody that activates Vy9V82 T cells. In vitro, in vivo, and ex vivo experiments were conducted, and safety was evaluated in nonhuman primates. The findings demonstrated the potential of the antibody to activate Vy9V82 T cells for antitumor activity and its acceptable safety profile, providing a solid basis for further testing in patients with EGFR-positive malignancies.
CANCER IMMUNOLOGY RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Patricia Himmels, Thi Thu Thao Nguyen, Maresa Caunt Mitzner, Alfonso Arrazate, Stacey Yeung, Jeremy Burton, Robyn Clark, Klara Totpal, Raj Jesudason, Angela Yang, Margaret Solon, Jeffrey Eastham, Zora Modrusan, Joshua D. Webster, Amy A. Lo, Robert Piskol, Weilan Ye
Summary: Preclinical and clinical studies show that T cell-dependent bispecific antibodies (TDBs) not only kill tumors but also cause systemic changes, leading to adverse events. In this study, the acute responses to TDBs in tumor-bearing mice were characterized in detail. The results reveal rapid and significant accumulation of lymphocytes and activation of endothelial cells (ECs) around large blood vessels in normal organs, particularly the liver. It is suggested that differential responses in normal tissues and tumors may be attributed to organ-specific ECs, and a list of genes selectively upregulated in large liver vessels by TDBs is identified. Furthermore, the study demonstrates that CD9 facilitates the interaction between T cells and ECs through the support of ICAM-1 in response to soluble factors released from TDB-mediated cytotoxic reactions. These findings provide insights into the response of different vascular beds to cancer immunotherapy and may contribute to improving their safety and efficacy.
Article
Immunology
Vinicio Melo, Levi Collin Nelemans, Martijn Vlaming, Harm Jan Lourens, Valerie R. Wiersma, Vrouyr Bilemjian, Gerwin Huls, Marco de Bruyn, Edwin Bremer
Summary: A bispecific antibody, CD27xEGFR, has been developed to re-activate T cell immunity in EGFR-expressing cancers through targeted co-stimulation of CD27. CD27xEGFR binds to both CD27 and EGFR simultaneously, triggering EGFR-restricted co-stimulation of T cells and enhancing T cell cytotoxicity against cancer cells. It has the potential to improve clinical outcomes in various cancers by overcoming the inhibitory factors that suppress T cell activity.
FRONTIERS IN IMMUNOLOGY
(2023)
Review
Oncology
Shujie Zhou, Mingguo Liu, Fei Ren, Xiangjiao Meng, Jinming Yu
Summary: T cell-based immunotherapies have revolutionized cancer treatment, but limited T-cell infiltration in tumor sites remains a major issue. BiTE therapy, a promising approach using bispecific antibodies to induce tumor lysis, has shown impressive efficacy in B cell malignancies but faces resistance mechanisms such as antigen loss and immune checkpoints upregulation. This highlights the need for modifying antibody constructs and developing combination strategies to enhance efficacy and reduce toxicity, particularly in solid tumors where response to BiTE therapy is poor.
BIOMARKER RESEARCH
(2021)
Article
Oncology
Mirco J. Friedrich, Paola Neri, Niklas Kehl, Julius Michel, Simon Steiger, Michael Kilian, Noemie Leblay, Ranjan Maity, Roman Sankowski, Holly Lee, Elie Barakat, Sungwoo Ahn, Niels Weinhold, Karsten Rippe, Lukas Bunse, Michael Platten, Hartmut Goldschmidt, Carsten Mueller-Tidow, Marc-Steffen Raab, Nizar J. Bahlis
Summary: Bispecific T cell engagers (TCEs) have shown promise in treating various cancers, but the immune mechanisms and molecular determinants of resistance to TCEs are still poorly understood. This study identifies conserved behaviors of bone marrow-residing T cells in multiple myeloma patients undergoing BCMAxCD3 TCE therapy and reveals the association between tumor recognition, exhaustion, and clinical response. The findings also highlight the significance of targeting exhausted-like CD8+ T cells and the loss of target epitope and MHC class I in tumor adaptation to TCEs. These insights advance our understanding of TCE treatment in humans and provide a basis for immune-monitoring and immunotherapy in hematological malignancies.
Review
Immunology
Gihoon You, Jonghwa Won, Yangsoon Lee, Dain Moon, Yunji Park, Sang Hoon Lee, Seung-Woo Lee
Summary: BsAbs are emerging as a growing class of immunotherapies with the potential to improve clinical efficacy and safety further. The review describes four classes of BsAbs and presents examples of BsAbs in development. With more data from clinical trials accumulating, BsAbs could be the next generation of new treatment options for cancer patients.
Article
Immunology
Ning Shi, Yangyihua Zhou, Yujun Liu, Ran Zhang, Xingjun Jiang, Caiping Ren, Xiang Gao, Longlong Luo
Summary: In this study, a novel bispecific antibody YG-003D3 targeting PD-1 and LAG-3 was designed, showing strong anti-tumor activity by activating immune cells more effectively. The antibody maintained similar affinity and thermal stability to the parental antibody, and could target multiple cells simultaneously to release the 'brake system of immune checkpoints'. The antibody also exhibited better ability to activate PBMC and alter the proportion of immune cells in the tumor microenvironment.
FRONTIERS IN IMMUNOLOGY
(2022)
Review
Immunology
Jingyue Kang, Tonglin Sun, Yan Zhang
Summary: Bispecific antibodies (bsAbs) are artificial antibodies that can bind to different antigens or different epitopes on the same antigen, thanks to their two distinct antigen-binding sites. They have shown significant potential in tumor treatment and have been extensively researched. Currently, 7 bsAbs have been approved for marketing worldwide, with over 200 bsAbs in various stages of clinical and preclinical research.
FRONTIERS IN IMMUNOLOGY
(2022)
Review
Oncology
Zheng Tian, Ming Liu, Ya Zhang, Xin Wang
Summary: Harnessing the power of immune cells, especially T cells, to enhance anti-tumor activities has become a promising strategy in clinical management of hematologic malignancies. Bispecific antibodies such as BiTEs have shown potential in recruiting T cells to tumor cells for immunotherapy, with a focus on improving efficacy and safety in clinical treatments for hematologic malignancies.
JOURNAL OF HEMATOLOGY & ONCOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Shuyu Huang, Aina Segues, Martin Waterfall, David Wright, Charlotte Vayssiere, Sander M. J. van Duijnhoven, Andrea van Elsas, Alice J. A. M. Sijts, Dietmar M. Zaiss
Summary: T cell engager (TCE) antibodies have shown promise as cancer therapeutics by linking cytotoxic T cells to tumor cells. This study evaluates a novel bispecific antibody format, Fab x sdAb-Fc, as a T-cell redirecting bispecific antibody (TbsAbs) and identifies the hinge design as a key factor influencing their anti-tumor activity.
Article
Oncology
Daisuke Kamakura, Ryutaro Asano, Hiroki Kawai, Masahiro Yasunaga
Summary: T cell-dependent bispecific antibody (TDB) induces T cell activation to eliminate tumor cells independently of MHC engagement, and may be a breakthrough immunotherapy for refractory cancer. The mechanism involves T cell-tumor cell contact for direct killing and cytokine secretion for contact-independent damage. TDB hEx3 shows promise against refractory CRC, targeting specific mutations and utilizing four action steps for tumor cell killing.
CANCER IMMUNOLOGY IMMUNOTHERAPY
(2021)
Article
Pharmacology & Pharmacy
Zhidi Pan, Jie Chen, Xiaodong Xiao, Yueqing Xie, Hua Jiang, Baohong Zhang, Huili Lu, Yunsheng Yuan, Lei Han, Yuexian Zhou, Huifang Zong, Lei Wang, Rui Sun, Jianwei Zhu
Summary: T cell engaging bispecific antibody (TCB) is an effective immunotherapy that redirects CD3(+) T cells to eliminate tumor cells without relying on T cell receptor specificity. In this study, a novel TCB targeting tissue factor (TF-TCB) was designed and characterized for the treatment of TF-positive tumors. TF-TCB induced robust T cell activation and proliferation, and effectively lysed tumor cells both in vitro and in vivo. Tumor growth was strongly inhibited by TF-TCB, and T cell infiltration into tumors was induced during the treatment. Combination with immune checkpoint inhibitors further improved the efficacy of TF-TCB.
ACTA PHARMACEUTICA SINICA B
(2022)
Article
Chemistry, Multidisciplinary
Wei-Jie Cheng, Kuo-Hsiang Chuang, Yu-Ju Lo, Michael Chen, Yi-Jou Chen, Steve R. Roffler, Hsiu-O Ho, Shyr-Yi Lin, Ming-Thau Sheu
Summary: In this study, a biocompatible nanocarrier system loaded with ganetespib was developed to enhance the efficacy of immunotherapies. The system, decorated with bispecific T-cell engagers, showed increased cellular uptake and synergistic effects in T cell-mediated cytotoxicity. In vivo studies also demonstrated tumor growth inhibition and increased T-cell infiltration. This study provides a promising drug delivery strategy for cancer immunochemotherapy.
JOURNAL OF CONTROLLED RELEASE
(2022)
Article
Oncology
Martina Svenja Lutz, Boris Klimovich, Stefanie Maurer, Jonas S. Heitmann, Melanie Maerklin, Latifa Zekri, Gundram Jung, Helmut R. Salih, Clemens Hinterleitner
Summary: This study found that platelet activation reduces the efficacy of T cell-recruiting antibodies, and the effect can be restored by blocking the transforming growth factor beta (TGF-beta) axis.
JOURNAL FOR IMMUNOTHERAPY OF CANCER
(2022)
Article
Chemistry, Multidisciplinary
Yumiao Chen, Wei Li, Zhongqiu Wang, Yingying Yu, Jie Li, Yinghao Ding, Zhiwen Hu, Qian Liu, Zhimou Yang, Jie Gao
Summary: This study introduces a novel cancer immunotherapy tool, Supra-BiCE, that enhances the binding of immune cells to tumor cells by transforming nanoribbons into nanofibrils, leading to the accumulation and activation of immune cells within tumor regions.
ADVANCED MATERIALS
(2023)
Review
Medicine, Research & Experimental
Antonio Tapia-Galisteo, Marta Compte, Luis alvarez-Vallina, Laura Sanz
Summary: Multispecific antibodies have the potential to overcome current limitations and have important implications in cancer therapy.
Article
Biochemistry & Molecular Biology
Ainara Cano, Mercedes Vazquez-Chantada, Javier Conde-Vancells, Aintzane Gonzalez-Lahera, David Mosen-Ansorena, Francisco J. J. Blanco, Karine Clement, Judith Aron-Wisnewsky, Albert Tran, Philippe Gual, Carmelo Garcia-Monzon, Joan Caballeria, Azucena Castro, Maria Luz Martinez-Chantar, Jose M. Mato, Huiping Zhu, Richard H. H. Finnell, Ana M. M. Aransay
Summary: Low serum folate levels are associated with metabolic associated fatty liver disease (MAFLD). The role of the folate transporter gene (SLC19A1) in lipid accumulation during the onset of MAFLD was assessed through genomic, transcriptomic, and metabolomic techniques. SNPs rs1051266 and rs3788200 were significantly associated with fatty liver development, and the lack of functional SLC19A1 affected gene regulation and lipid metabolism, leading to lipid droplet accumulation in hepatocytes.
Article
Multidisciplinary Sciences
Jingyi Zhao, Vincent DiGiacomo, Mariola Ferreras-Gutierrez, Shiva Dastjerdi, Alain Ibanez de Opakua, Jong-Chan Park, Alex Luebbers, Qingyan Chen, Aaron Beeler, Francisco J. Blanco, Mikel Garcia-Marcos
Summary: IGGi-11 selectively inhibits noncanonical activation of heterotrimeric G-protein signaling, blocking tumor cell signaling and inhibiting metastatic cancer cell invasion without interfering with canonical GPCR signaling mechanisms.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Oncology
Laura Rubio-Perez, Rodrigo Lazaro-Gorines, Seandean L. Harwood, Marta Compte, Rocio Navarro, Antonio Tapia-Galisteo, Jaume Bonet, Belen Blanco, Simon Lykkemark, Angel Ramirez-Fernandez, Mariola Ferreras-Gutierrez, Carmen Dominguez-Alonso, Laura Diez-Alonso, Alejandro Segura-Tudela, Oana Hangiu, Ainhoa Erce-Llamazares, Francisco J. Blanco, Cruz Santos, Jose L. Rodriguez-Peralto, Laura Sanz, Luis Alvarez-Vallina
Summary: In this study, a PD-L1/EGFR symmetric bispecific antibody was developed, which could simultaneously inhibit EGFR-mediated proliferation, effectively block PD-1/PD-L1 interaction, and induce strong antigen-specific antibody-dependent cellular cytotoxicity activity in vitro. Potent therapeutic efficacies of this antibody were observed in two different humanized mouse models.
Review
Oncology
Antonio Tapia-Galisteo, Luis alvarez-Vallina, Laura Sanz
Summary: Immune cell engagers are modified antibodies that have one arm binding a tumor-associated antigen and another arm binding an activating receptor in immune effector cells. These engagers have the potential to revolutionize the treatment of hematological malignancies and are more potent than conventional monoclonal antibodies. The field is growing rapidly, with multiple formats and targets currently in clinical trials, and trispecific antibodies show even more promise by targeting additional tumor-associated antigens or costimulatory receptors.
JOURNAL OF HEMATOLOGY & ONCOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Rodrigo Lazaro-Gorines, Patricia Perez, Ignacio Heras-Murillo, Irene Adan-Barrientos, Guillermo Albericio, David Astorgano, Sara Flores, Joanna Luczkowiak, Nuria Labiod, Seandean L. Harwood, Alejandro Segura-Tudela, Laura Rubio-Perez, Yudhi Nugraha, Xiaoran Shang, Yuxing Li, Carlos Alfonso, Kaylin A. Adipietro, Dinendra L. Abeyawardhane, Rocio Navarro, Marta Compte, Wenbo Yu, Alexander D. Mackerell, Laura Sanz, David J. Weber, Francisco J. Blanco, Mariano Esteban, Edwin Pozharski, Raquel Godoy-Ruiz, Ines G. Munoz, Rafael Delgado, David Sancho, Juan Garcia-Arriaza, Luis Alvarez-Vallina
Summary: In this study, a broadly neutralizing antibody (nAb) TNT was generated, which showed high-avidity neutralizing interaction by simultaneously binding to all six RBD epitopes. By fusing an anti-DNGR-1 scFv to TNT, a bispecific trimerbody TN(T)DNGR-1 was generated, which targeted neutralized virions to cDC1s and promoted T cell cross-priming. Therapeutic administration of TN(T)DNGR-1 protected mice from lethal SARS-CoV-2 infection and enhanced virus-specific humoral and CD8(+) T cell responses.
Article
Biochemistry & Molecular Biology
Javier Narbona, Luisa Hernandez-Baraza, Ruben G. Gordo, Laura Sanz, Javier Lacadena
Summary: Immunotoxins are chimeric molecules that combine the specificity of an antibody-based targeting domain and the cytotoxic potency of a toxin. This study designed and characterized several immunotoxin constructs using nanobodies as targeting domains against EGFR. The results confirm the therapeutic potential of a-sarcin-based nanoITXs.