Review
Oncology
Alison Crawford, Danica Chiu
Summary: Immunotherapies for cancer treatment have progressed significantly in the past decade, with a focus on T cell-directed therapies such as CD3 bispecific antibodies and CAR T cells. However, the application of these therapies to solid tumors remains a challenge, with ongoing research needed to overcome resistance mechanisms.
MOLECULAR CANCER THERAPEUTICS
(2021)
Article
Oncology
Sisi Wang, Lijun Peng, Wenqian Xu, Yuebo Zhou, Ziyan Zhu, Yushan Kong, Stewart Leung, Jin Wang, Xiaoqiang Yan, Jian-Qing Mi
Summary: The newly designed antibodies A-319 and A-2019 showed potent antitumor effects in vitro, ex vivo, and in vivo experiments. A-319 and A-2019 are CD3/CD19 and CD3/CD19/CD20 bispecific and trispecific antibodies, respectively, capable of recruiting T cells, enhancing T-cell function, mediating B-cell depletion, and inhibiting tumor growth.
FRONTIERS OF MEDICINE
(2022)
Article
Oncology
Helene Bonnevaux, Stephane Guerif, Jana Albrecht, Erwan Jouannot, Thibaud De Gallier, Christian Beil, Christian Lange, Wulf Dirk Leuschner, Marion Schneider, Cendrine Lemoine, Anne Caron, Celine Amara, Cedric Barriere, Justine Siavellis, Valerie Bardet, Ernesto Luna, Pankaj Agrawal, Donald R. Drake, Ercole Rao, Peter Wonerow, Chantal Carrez, Veronique Blanc, Karl Hsu, Dmitri Wiederschain, Paula G. Fraenkel, Angela Virone-Oddos
Summary: CD123-CODV-TCE, a bispecific antibody, shows promising preclinical activity against AML by effectively targeting CD123 on malignant cells and inducing T-cell directed killing, suggesting it as a potential therapy for patients with relapsed/refractory AML.
Article
Oncology
Lijun Wu, Yanwei Huang, John Sienkiewicz, Jinying Sun, Liselle Guiang, Feng Li, Liming Yang, Vita Golubovskaya
Summary: This study investigated novel bispecific antibodies targeting multiple myeloma and found that they demonstrated high efficacy in killing multiple myeloma cells, providing a basis for future clinical studies.
Article
Biotechnology & Applied Microbiology
Pingyan Cheng, Xianghong Chen, Robert Dalton, Alexandra Calescibetta, Tina So, Danielle Gilvary, Grace Ward, Victoria Smith, Sterling Eckard, Judith A. Fox, Jeanmarie Guenot, Joseph Markowitz, John L. Cleveland, Kenneth L. Wright, Alan F. List, Sheng Wei, Erika A. Eksioglu
Summary: This study found that MDSCs play an important role in the pathogenesis of MDS, and depletion of MDSCs may improve resistance to checkpoint inhibitors. Combination of AMV564 with anti-PD1 enhances the activation of cytotoxic T cells, showing potential for improving therapeutic efficacy.
Review
Oncology
Jim Middelburg, Kristel Kemper, Patrick Engelberts, Aran F. Labrijn, Janine Schuurman, Thorbald van Hall
Summary: CD3-bispecific antibody therapy is a rapidly developing field in immunotherapy, with approved use in hematological malignancies and ongoing research in solid tumors. However, treatment of solid tumors faces more challenges, including increased on-target off-tumor toxicities, sparse T-cell infiltration, and impaired T-cell quality due to an immunosuppressive tumor microenvironment, affecting the safety and efficacy of CD3-bispecific antibody therapy. Various combinatorial approaches are being explored to overcome these hurdles and improve the selectivity and effectiveness of the therapy.
Article
Immunology
Ryan D. D. Molony, Theresa Funk, Gina Trabucco, Erik Corcoran, David Ruddy, Malini Varadarajan, GiNell Elliot, Michelle Piquet, Joni Lam, Matthew J. J. Meyer, Hui Qin Wang, Sema Kurtulus, Haihui Lu
Summary: CD3-engaging bispecific antibodies (BsAbs) enable killing of target cells by forming an immune synapse between T cells and tumor cells, without relying on preexisting tumor specific T cell receptor. It has been found that CD8+ T cells depend on signaling factors derived from CD4+ T cells to achieve sustained killing. The mammalian target of rapamycin (mTOR) pathway and other candidate genes have been identified as intrinsic regulators of BsAb-induced T cell proliferation and/or activation.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Oncology
Ze Tian, Chunhua Shi, Guojun Yang, Jason K. Allen, Qing Shi, Amin AI-Shami, Jill Wardell Olson, Melinda G. Smith, Qing Chang, Jasbir Kaur, Junping You, Timothy E. Lofton, Michelle A. Gonzalez, Qi Zhang, DongXing Zha, Sarah K. Tasian, Nitin Jain, Marina Y. Konopleva, Timothy Heffernan, Jeffrey J. Molldrem
Summary: Patients with CRLF2-rearranged B-ALL have a low 5-year survival rate, and there is a need for therapeutic options with improved duration of response. Our research found that patients with CRLF2-rearranged Ph-like ALL have elevated expression of TSLPR, comparable to CD19. We demonstrated that a novel CD3-redirecting bispecific antibody, 1B7/CD3, exhibits potent T cell activation and tumor lytic activity, both in vitro and in vivo, providing a potential clinical evaluation for patients with CRLF2-rearranged B-ALL.
Article
Oncology
George S. Laszlo, Johnnie J. Orozco, Allie R. Kehret, Margaret C. Lunn, Jenny Huo, Donald K. Hamlin, D. Scott Wilbur, Shannon L. Dexter, Melissa L. Comstock, Shyril O'Steen, Brenda M. Sandmaier, Damian J. Green, Roland B. Walter
Summary: This study developed At-211-based RIT targeting CD123, demonstrating potent and target-specific anti-leukemia efficacy in mouse models.
Article
Oncology
Si-Qi Liu, Alyssa Grantham, Casey Landry, Brian Granda, Rajiv Chopra, Srinivas Chakravarthy, Sabine Deutsch, Markus Vogel, Katie Russo, Katherine Seiss, William R. Tschantz, Tomas Rejtar, David A. Ruddy, Tiancen Hu, Kimberly Aardalen, Joel P. Wagner, Glenn Dranoff, Joseph A. D'Alessio
Summary: The study revealed that deficiency in IFN-gamma signaling plays a key role in cancer resistance, and core fucosylation is a critical pathway to regulate the binding of CD3-bispecific antibodies to the CD123 antigen. These findings contribute to enhancing the clinical potential of current and future T-cell-engaging CD3-bispecific antibody therapies.
CANCER IMMUNOLOGY RESEARCH
(2021)
Article
Immunology
Eline van Diest, Mara J. T. Nicolasen, Lovro Kramer, Jiali Zheng, Patricia Hernandez-Lopez, Dennis X. Beringer, Jurgen Kuball
Summary: In this study, we developed a novel T cell engager concept called GAB by utilizing γδTCR as a tumor targeting domain. The γδ ECTO-alpha CD3-dimer design was found to be superior in function compared to monomers and does not induce T cell activation without simultaneous tumor engagement.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Medicine, Research & Experimental
Liping Zhong, Wei Shi, Lu Gan, Xiuli Liu, Yu Huo, Pan Wu, Zhikun Zhang, Tao Wu, Hongmei Peng, Yong Huang, Yongxiang Zhao, Yulin Yuan, Zhiming Deng, Hongliang Tang
Summary: A bispecific T-cell engager antibody targeting human endoglin and CD3 was constructed in this study, showing therapeutic potential in cancer treatment. In vivo experiments demonstrated that the antibody significantly reduced tumor growth and neoangiogenesis, leading to improved mouse survival.
Article
Medicine, Research & Experimental
Michael Boyiadzis, Pinkal Desai, Nikki Daskalakis, William Donnellan, Lucille Ferrante, Jenna D. Goldberg, Michael R. Grunwald, Christina Guttke, Xiang Li, Jose Antonio Perez-Simon, Olga Salamero, Trevor Tucker, Xiaoying Xu, Jay Yang, Naveen Pemmaraju, Juan Manuel Alonso-Dominguez
Summary: This study aimed to identify a recommended phase II dose of JNJ-63709178 and assess its safety, tolerability, pharmacokinetics/pharmacodynamics, and preliminary clinical activity in patients with relapsed or refractory acute myeloid leukemia. The results revealed suboptimal drug exposure, unfavorable safety profiles, and limited clinical activity for both intravenous and subcutaneous administration of JNJ-63709178.
CTS-CLINICAL AND TRANSLATIONAL SCIENCE
(2023)
Article
Oncology
Vincenzo Maria Perriello, Ilaria Gionfriddo, Roberta Rossi, Francesca Milano, Federica Mezzasoma, Andrea Marra, Orietta Spinelli, Alessandro Rambaldi, Ombretta Annibali, Giuseppe Avvisati, Francesco Di Raimondo, Stefano Ascani, Brunangelo Falini, Maria Paola Martelli, Lorenzo Brunetti
Summary: One-third of adult AML patients have NPM1 mutations, with high expression of CD123 identified as a potential target for therapy in NPM1-mutated leukemic cells, particularly in CD34(+)CD38(-) cells. Targeting CD123 may be effective for treating NPM1-mutated AML, especially in combination with FLT3 mutations.
Article
Multidisciplinary Sciences
Nadia El Khawanky, Amy Hughes, Wenbo Yu, Renier Myburgh, Tony Matschulla, Sanaz Taromi, Konrad Aumann, Jade Clarson, Janaki Manoja Vinnakota, Khalid Shoumariyeh, Cornelius Miething, Angel F. Lopez, Michael P. Brown, Justus Duyster, Lutz Hein, Markus G. Manz, Timothy P. Hughes, Deborah L. White, Agnes S. M. Yong, Robert Zeiser
Summary: The success of CAR-T cells in treating AML is constrained by their toxicity to normal cells and low persistence. This study demonstrates that the demethylating compound 5'-Azacitdine can enhance anti-CD123 CAR-T cell cytotoxicity against AML cells. Additionally, the development of third-generation anti-CD123 CAR-T cells shows promising results in targeting AML cells without affecting healthy hematopoietic system.
NATURE COMMUNICATIONS
(2021)