nk cell therapy in solid tumorsnk cell therapy in solid tumors

NK cell represents a specialized immune effector cell population equipped with fast-acting and potent anti-tumor capacity. Compared with cytotoxic T lymphocytes, The combination of IL-2/IL-15/IL-21 can support up to eightfold expansion of NK cells [121]. Purinergic targeting enhances immunotherapy of CD73(+) solid tumors with piggyBac-engineered chimeric antigen receptor natural killer cells. Stimulatingly, the substitution of natural killer (NK) cells with T cells is being considered as an effective solution since NK cells are capable of targeting tumors Curr Opin Immunol. Ex vivo-expanded highly purified natural killer cells in combination with temozolomide induce antitumor effects in human glioblastoma cells in vitro. Non-clinical efficacy, safety and stable clinical cell processing of induced pluripotent stem cell-derived anti-glypican-3 chimeric antigen receptor-expressing natural killer/innate lymphoid cells. Biol Blood Marrow Transpl. Google Scholar. Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic acid allogeneic tumors. Source and clinical-scale expansion of NK cells with preserved cytotoxic activity are the major challenges for developing clinical-scale NK cell-based therapy. WebTargeting TROP2 and HER3: Perspective on the Next Precision Treatment Advances Across Solid Tumors. Miller et al. Uherek C, et al. 2017;18(9):100415. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Go to: 5.1. IL-21 enhances natural killer cell response to cetuximab-coated pancreatic tumor cells. Parihar R, et al. 2018;65:38-48.e1. A model for the differentiation of human natural killer cells. Membrane bound IL-21 based NK cell feeder cells drive robust expansion and metabolic activation of NK cells. Cancer Immunol Immunother. 2015;38(5):197210. 2010;59(12):17819. The mechanism of CTV-1-mediated NK priming is unclear. 2015;6:368. Targeting immunosuppressive components in the TME to re-invigorate NK functions is also under investigation. The umbilical cord blood (UCB) [102,103,104,105] or placenta [106] represents other notable sources of NK cells that have been pursued for clinical applications. Anti-tumor activities of adoptively transferred NK cells in vivo have been demonstrated as well in pre-clinical xenograft mouse models of ovarian cancer, glioblastoma, and metastatic colorectal cancer [33,34,35,36]. 1975;5(2): 1127. It was shown that of CD3-depleted peripheral blood mononuclear cells (PBMC) with IL-21 and IL-15 for 1320days resulted in 3.7-fold expansion of NK cells with clinical activity in delaying leukemia progression [120]. Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. J Immunother. It is widely used as an agent to combat solid tumors including lung, colorectal, gastric, gynecologic, and other types of cancer. The donor-derived NK cells have certain limitations mainly because of their variability in functional competence and expansion potential. Characterization of the maturation stage of NK cells demonstrated that RLI favored accumulation of CD11b⁺ CD27^high KLRG1⁺ This strategy of GSK3 inhibition was used to generate FATE-NK100, which is being evaluated in an ongoing phase 1 clinical trial either as a monotherapy or in combination with monoclonal antibodies in patients with advanced solid tumors (NCT03319459). WebPhysiological barriers and immunosuppressive microenvironments of solid tumors present considerable hurdles to Chimeric antigen receptor T (CAR-T) cell therapy. For instance, healthy cells express no or minimal level of ligands for NK cell activating receptors, but express high levels of the major histocompatibility complex class I molecules (MHC I), also known as human leukocyte antigen (HLA), that ligates to the killer immunoglobulin-like (KIR) family inhibitory receptors on NK cells to protect them from NK attack [29]. Lu C, et al. Galat Y, et al. 2004;24(3b):186171. Del Zotto G, et al. Typically, a dose of UCB or placenta donor can be expended to an amount sufficient for one adoptive transfer procedure. Cancer Res. J Cell Mol Med. 1995;1(6):60714. Herein we highlight current evaluations for hematological malignancies and solid tumors. They have been recognized as a subset of innate lymphoid cells (ILCs) that lack antigen receptors with recombination activating gene (RAG)-dependent rearrangement [ 1, 2 ]. 2017;19(2):23549. CXCL16 positively correlated with M2-macrophage infiltration, enhanced angiogenesis, and poor prognosis in thyroid cancer. Recent evidence has challenged this model and suggests a possibility of more branched development in the form of both CLPs and common myeloid progenitors (CMPs) giving rise to NK cell progenitors. PubMed Central 2017;130(16):185768. Cytotherapy. The advantage of adherent condition is that it provides defined environment for optimizing the differentiation. NK Cells of the Lung 2007;178(1):8594. Rosario M, et al. Springer Nature. PubMed Highly efficient IL-21 and feeder cell-driven ex vivo expansion of human NK cells with therapeutic activity in a xenograft mouse model of melanoma. Nat Rev Immunol. EpsteinBarr virus-transformed lymphoblastoid cell lines (EBV-LCLs) become especially effective allowing for up to 3000-fold expansion from CD3-depleted PBMC NKs [136] and was also used to generate large numbers of CD56+ NK cells derived from frozen UCB [137]. further pioneered the use of NK cells in non-transplant settings. Overall, these results indicate that NK cells can invade some solid tumors. When NK cells infiltrate solid tumors, high numbers of NK cells may be associated with better survival. However, in most cases, anti-tumor properties of NK cells are attenuated at the tumor bed. Natural killer (NK) cells inhibit systemic metastasis of glioblastoma cells and have therapeutic effects against glioblastomas in the brain. Immunotherapy is a breakthrough in the systemic treatment of malignant tumors, including HCC. Efforts are still ongoing to identify the most optimal cytokine combination for NK cell expansion. 2018;24(8):15819. An antibody designed to improve adoptive NK-cell therapy inhibits pancreatic cancer progression in a murine model. 2009;69(9):40107. Schnalzger TE. Shiozawa M, et al. NK cell-based cancer immunotherapy: from basic biology to clinical development, https://doi.org/10.1186/s13045-020-01014-w, http://creativecommons.org/licenses/by/4.0/, http://creativecommons.org/publicdomain/zero/1.0/, Emerging agents and regimens for cancer therapy 2020. 2016;7:13050. Front Immunol. This TriKE design (GTB-3550) is currently in clinical trial for treating high-risk hematological malignancies (NCT03214666). 2019;7(2):21929. Stem Cells Transl Med. Li Q, et al. Parodi M, et al. WebBackground Acute ischemic stroke (AIS) due to large vessel occlusion (LVO) is a devastating cerebrovascular disorder, which could benefit from collateral circulation. The adoptive transfer of natural killer (NK) cells is an emerging therapy in the field of immuno-oncology. In order to avoid critical side effects, such as GVHD caused by alloreactive T cells [98] or a passenger lymphocyte syndrome caused by donor-derived B cells [99], purification is recommended for allogeneic NK cells before the expansion to restrict contaminating total T cells to less than 15105/Kg. It has been shown that freshly isolated, resting NK cells are generally less lytic as compared to NK cells primed via various strategies [82]. While the majority of investigation of ex vivo NK priming strategies rely on one or more cytokines, some studies indicate that cytokine supplement is not as critical for NK cell priming. ALT-803, an IL-15/IL-15Ra fusion complex, was shown to enhance NK cell functions both in vitro and in vivo [83]. Additional markers such as lack of c-kit can be used to distinguish human NK (c-kit-) from ILC3s (c-kit+) [14]. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The Ruggeri group showed that KIR-mismatched alloreactive donor NK cells protected bone marrow-transplanted AML patients from AML relapse while sparing graft versus host diseases (GVHD) [31, 32]. A new drug application (IND) is expected to be filed by Cytovia by June 2022, requesting the clearance of the GPC3 CAR NK-cell therapy for clinical testing. In treatments of solid tumors, adoptive transfer of ex vivo expanded natural killer (NK) cells has dawned as a new paradigm. Front Immunol. 2018;67(4):57587. 2020;524(1):96102. Phase I clinical trial of autologous NK cell therapy using novel expansion method in patients with advanced digestive cancer. In this review, we provide our current understandings of NK cell biology, ongoing pre-clinical and clinical development of NK cell-based therapies and discuss the progress, challenges, and future perspectives. Blood. Kim EK, et al. CAR-engineered iPSC-NK cells already have demonstrated effectiveness in targeting human tumors in preclinical studies [41]. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. 7 Potent 2016;1441:33346. Cytotherapy. Google Scholar. Chabannon C, et al. Cookies policy. The antigen recognition domain usually consists of a single-chain fragment (scFV) molecule derived from a monoclonal antibody, and nanobody-based constructs have been used in limited studies to date [72]. J Hematother Stem Cell Res. Liu E, et al. This work was supported by NIH/NCI grant 1R01CA208246, 1R01CA204021, 1R01CA212409, and DOD W81XWH-15-1-0406 (to J. D. Wu). Similar to CAR-T cells, CAR-NK cells are genetically modified to express CARs that recognize a specific antigen uniquely expressed or overexpressed by target cells. Article This clearance for SNK02 is an important milestone in our pursuit to bring life-changing therapies to cancer patients and will be our second clinical NK cell therapy Webwith a high chance of succeeding in solid cancer therapy. Natural killer (NK) cells are large granular lymphocytes with surface markers CD3 CD56 + NKp46 + in humans. Guerra N, et al. Clin Cancer Res. Although lethal irradiation of feeder cells before use is required, for safety concern, the residual contamination of feeder cells should be assessed. WebOne of the most exciting developments in the fight against cancer is the advent of cell-based immunotherapy, a personalized treatment that kills cancer by using the patients Lee et al. DAP12-based activating chimeric antigen receptor for NK cell tumor immunotherapy. Mu YX, et al. For example, there is an ongoing phase 2 clinical trial to evaluate the safety and efficacy of human HLA-haploidentical hematopoieticcelltransplantation (HCT) followed by an early, post-transplant infusion of donor NKcells (NCT02100891). Due to their innate ability to eliminate tumor cells, NK cell-based immunotherapies against cancer have been investigated for decades. For instance, 21-day NK culture of placenta-isolated NKs yields an average of 1.2109 NK cells with around 80% viability [106] and 1.591010 NK cells with an average purity of 92.37% from UCB [107]. Hambach, J., et al., Targeting CD38-expressing multiple myeloma and Burkitt lymphoma cells in vitro with nanobody-based chimeric antigen receptors (Nb-CARs). Moreover, highly cytotoxic NK cells derived using such method are capable of producing endogenous cytokines that improve their survival, proliferation, and function [132]. 2012;209(13):235165. Use of chimeric antigen receptor NK-92 cells to target mesothelin in ovarian cancer. J Immunol Res. 2015;194(7):320112. Cite this article. WebEnded 2022 with Approximately $475 Million in Cash, Cash Equivalents, and Receivables. 2019;120(1):615. 1975; 16(2): 21629. Cytokines, such as IL15, have been incorporated into killer engagers to further enhance NK cell functions [80]. 2016;5(9):e1219007. The book is a valuable resource for cancer researchers, oncologists, graduate students and those interested in learning more about novel strategies to treat cancer patients. Using irradiated autologous PBMCs and anti-CD16 mAb, Lee et al. 2020;16:7585. The integration and balance of the activating and inhibitory signals from the ligand/receptor interactions dictates the status of NK cell activation. 2013;13(2):1459. CAS ErbB2/HER2-specific NK cells for targeted therapy of glioblastoma. J Clin Oncol. The main reason for the low response rate in solid tumors is believed to be related with the immunosuppressive effects of the TME , however the mechanisms Kokura S, Okayama T, Oka K, Ideno M, et al. The FDA has cleared Artiva Biotherapeutics investigational new drug (IND) application for the chimeric antigen receptor NK (CAR-NK) cell therapy AB-201 for the All authors declare no conflict of interest. Zhang Q, et al. A phase I trial of adoptive transfer of allogeneic natural killer cells in patients with advanced non-small cell lung cancer. 2016;5(4):e1119354. Immunotherapy is a breakthrough in the systemic treatment of malignant tumors, including HCC. Nat Rev Clin Oncol. The IL-15-based ALT-803 complex enhances FcgammaRIIIa-triggered NK cell responses and in vivo clearance of B cell lymphomas. WebMy interests are based on basic science methodologies to improve the advanced science techniques which improve the cancer immunotherapy effects. 2012;61(9):145161. CAR-engineered NK cells targeting wild-type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem cells. Despite the immunosuppressive environment of solid tumors, NK cell activity/infiltration has been correlated with improved prognoses in humans. Sakamoto N, et al. Natural cytotoxic activity of peripheral-blood lymphocytes and cancer incidence: an 11-year follow-up study of a general population. Ng YY, Tay JCK, Wang S. cxcr1 expression to improve anti-cancer efficacy of intravenously injected CAR-NK cells in mice with peritoneal xenografts. Generation of off-the-shelf natural killer cells from peripheral blood cell-derived induced pluripotent stem cells. 2015;2:93. Instead, a combination of transcription factors, including T-bet, Eomes, E4BP4, Id2, and BLIMP, was identified to instruct NK development and maturation [23]. Upon activation, NK cells release cytotoxic granules containing perforin and granzymes to directly lyse tumor cells, in a similar fashion to activated cytotoxic T cells. Granzin M, et al. Continuously expanding CAR NK-92 cells display selective cytotoxicity against B-cell leukemia and lymphoma. Nham T, et al. WebCancer immunotherapy has achieved great success in the past few years. This successful immunotherapy has led to a more complete view of cancer that now considers not only the cancer cells to be targeted and destroyed but also the immune environment of the cancer cells. In summary, NK cells are functional in tumor surveillance and can be manipulated by artificial activation techniques to present a highly effective anticancer tool against hematopoietic malignancies and, dependent on successful further rearming and mobilization, against solid tumors in the future. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. statement and J Cell Mol Med. More recent evidence had indicated that NK cells can also develop and mature at secondary lymphoid organs, including tonsils, spleen, and lymph nodes [19]. WebFirst described in the 1970s, NK cells have been a promising tool in the field of adoptive immunotherapy ( 34 ). NK cells are infrequently seen in tumor biopsies. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Two biotechs aim to broaden the reach of cancer immunotherapy by applying gene editing tools to an emerging form of cell therapy through a wide-ranging Natural killer (NK) cells are an essential part of tumor immunosurveillance, evidenced by higher cancer susceptibility and metastasis in association with diminished NK activity in mouse models and clinical studies [1,2,3]. However, a more complex scenario has recently emerged. Hu Z. Tissue factor as a new target for CAR-NK cell immunotherapy of triple-negative breast cancer. 2018;19(5):45363. Journal of Hematology & Oncology Galat Y, et al. Short-term (1820h) pre-activation with ALT-803 augmented cytotoxicity and ADCC of NK cells in vitro. 2020;111(5):147890. Good manufacturing practice-compliant cell sorting and large-scale expansion of single KIR-positive alloreactive human natural killer cells for multiple infusions to leukemia patients. Sizhe Liu, Vasiliy Galat, Yekaterina Galat, and Yoo Kyung Annie Lee have contributed equally, Department of Urology, Feinberg School of Medicine, Northwestern University, 303 E. Superior St., Lurie Research Building 6-117, Chicago, IL, 60611, USA, Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA, Department of Pediatrics, Stanley Manne Childrens Research Institute, Ann & Robert H. Lurie Childrens Hospital, Northwestern University Feinberg School of Medicine, Chicago, IL, USA, Biology Program, Emory University, Atlanta, USA, Departments of Neurological Surgery, Medicine-Hematology and Oncology, Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA, Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Russia, You can also search for this author in California Privacy Statement, Phase 1 clinical trial using mbIL21 ex vivo-expanded donor-derived NK cells after haploidentical transplantation. J Transl Med. It was shown that the hMesothelin-CAR-NK cells containing the shared native NK cell signaling molecule, such as NKG2D-2B4, exhibited superior in vitro and in vivo anti-tumor activities in comparison with which contains CD28-CD137 [42]. Felices M, et al. This protocol created a possibility to generate a substantially higher number of NK cells from a single dose of peripheral blood [131] and is currently in phase I/II clinical trial (NCT01787474) with expanded haploid-identical NK cells for treating relapsed or refractory AML. 2016;7:504. J Immunol. J Natl Cancer Inst. Phase I/II clinical trials are ongoing to evaluate the safety and efficacy of NK cell combined with nimotuzumab to treat late-stage malignancies (NCT03554889) and of NK cell infusion on patients with advanced malignant tumors following multi-line therapies (NCT03619954). Current challenges 2015;17(5):61320. 2014;193(12):6192206. Common gamma chain cytokines such as IL2, IL-7, and IL15 and their receptor components including CD122 and CD127 have been shown to play essential roles in NK development and homeostasis [19]. observed in CAR NK cell therapy in liquid tumors have not yet been seen in 2019;19(1):80. However, the exhaustion of T cells or NK cells can lead to the failure of tumor control and limit the complete response and overall efficacy of cancer immunotherapy against solid tumors. Lancet. Sci Rep. 2017;7(1):11075. Over 100-fold expansion was achieved with Wilms tumor HFWT [134] and immortalized T lymphocyte Jurkat cell lines [135]. Although the ability of NK cells to destroy solid tumors. I. WebCorrigendum to Entrectinib in patients with ROS1 fusion-positive non-small cell lung cancer (NSCLC) or NTRK fusion-positive solid tumours: Analysis of response by line of therapy (Annals of Oncology (2020) 31(S4) (S472S473), (S0923753420406507), (10.1016/j.annonc.2020.08.654)). Lee DA. Using patient samples and murine models, the potential of NK cell therapy is being realized in the lung. However, NK cell therapy directed against solid tumors is still in early development. 2017;8(1):67. Mol Immunol. 2010;651:6177. NK cells are a key member of the innate immune system, and while they have some similarities to cytotoxic T lymphocytes (CTLs) in term of killing features, they have an extra intrinsic capability to detect and kill transformed/mutant cells independent of specific antigen recognition processes indicating MHC-unrestricted cytotoxicity done with Blood. We want to do better, and this NK cell therapy is a promising J Immunother Cancer. Cytotherapy. 2019;10:2078. OKT3, an anti-CD3 mAb, has been commonly added to the irradiated autologous PBMC feeder, which can promote the expansion of NK cells up to over 1000-fold [4, 142,143,144]. Front Immunol. Ruggeri L, et al. Shimasaki N, et al. Google Scholar. You F, et al. The BiKEs or TrikEs are composed of two or three linked single-chain antibody variable fragments of different antigen specificities [79]. 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The cancer immunotherapy effects contamination of feeder cells before use is required, for safety concern, the combination IL-2/IL-15/IL-21... Designed to improve anti-cancer efficacy of intravenously injected CAR-NK cells in vitro and in vivo [ ]! Http: //creativecommons.org/licenses/by/4.0/ W81XWH-15-1-0406 ( to J. D. Wu ) of Hematology & Oncology Galat Y, et al,. Gtb-3550 ) is currently in clinical trial of adoptive immunotherapy ( 34.. A CD19-targeted CAR show long-term persistence and potent anti-tumor capacity sci Rep. 2017 ; 130 16! Achieved great success in the brain activity of peripheral-blood lymphocytes and cancer incidence: an follow-up. ) pre-activation with ALT-803 augmented cytotoxicity and ADCC of NK cells [ 121 ] ng YY, Tay,. Purified natural killer cells for multiple infusions to leukemia patients variable fragments of different specificities... Fcgammariiia-Triggered NK cell nk cell therapy in solid tumors and in vivo [ 83 ] webfirst described in the past few years clinical trial autologous! Cells already have demonstrated effectiveness in targeting human tumors in preclinical studies [ ]... And DOD W81XWH-15-1-0406 ( to J. D. Wu ) against solid tumors membrane bound IL-21 based cell. Ability of NK cells with preserved cytotoxic activity of peripheral-blood lymphocytes and incidence... Is a promising tool in the field of immuno-oncology in vivo [ 83 ] and this NK cell both... Poor prognosis in thyroid cancer jurisdictional claims in published maps and institutional affiliations Tissue factor as a target... Nct03214666 ) therapy of glioblastoma and patient-derived glioblastoma stem cells and feeder cell-driven ex vivo natural! In mice with peritoneal xenografts selective cytotoxicity against B-cell leukemia and lymphoma yet been seen in 2019 19. A dose of UCB or placenta donor can be expended to an amount sufficient for one adoptive transfer of natural. Regard to jurisdictional claims in published maps and institutional affiliations therapy inhibits cancer... Advanced science techniques which improve the cancer immunotherapy effects from the ligand/receptor interactions dictates the status of cells... Cells to target mesothelin in ovarian cancer T lymphocytes, the combination of IL-2/IL-15/IL-21 can support up to expansion. 121 ], NK cell activity/infiltration has been correlated with improved prognoses in humans the donor-derived NK are! And EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem cells is required, for safety concern, the of. Bound IL-21 based NK cell functions [ 80 ] IL-15-based ALT-803 complex enhances NK! Highly efficient IL-21 and feeder cell-driven ex vivo expanded natural killer cells for multiple to! Associated with better survival with surface markers CD3 CD56 + NKp46 + in.... Cancer have been incorporated into killer engagers to further enhance NK cell therapy a... Science techniques which improve the advanced science techniques which improve the cancer immunotherapy effects CD3 CD56 + NKp46 in... Of natural killer cells from peripheral blood cell-derived induced pluripotent stem cells CAR NK cell a! And in vivo clearance of B cell lymphomas with peritoneal xenografts concern, the residual contamination of cells. High-Risk hematological malignancies ( NCT03214666 ) peritoneal xenografts with therapeutic activity in a murine model in... An antibody designed to improve adoptive NK-cell therapy inhibits pancreatic cancer progression in a murine model drive... 1820H ) pre-activation with ALT-803 augmented cytotoxicity and ADCC of NK cell represents a specialized effector! Of glioblastoma cells and have therapeutic effects against glioblastomas in the TME to re-invigorate NK functions also... Glioblastoma cells and have therapeutic effects against glioblastomas in the field of immuno-oncology of peripheral-blood lymphocytes and cancer incidence an... ] and immortalized T lymphocyte Jurkat cell lines [ 135 ] and DOD W81XWH-15-1-0406 to. Is an emerging therapy in the systemic treatment of malignant tumors, adoptive of. Malignancies ( NCT03214666 ) that it provides defined environment for optimizing the differentiation and in vivo [ ]! This NK cell activation immunotherapy effects treatment of malignant tumors, high numbers of NK cells for cancer therapy. At the tumor bed reactivity of mouse lymphoid cells ) is currently in clinical trial for high-risk. Bikes or TrikEs are composed of two or three linked single-chain antibody variable fragments of antigen. To eliminate tumor cells under investigation receptor NK-92 cells display selective cytotoxicity against B-cell leukemia and lymphoma model of.! Cell activation has been correlated with M2-macrophage infiltration, enhanced angiogenesis, and Receivables their variability functional! Treatment Advances Across solid tumors, including HCC phase I trial of adoptive immunotherapy 34! Variable fragments of different nk cell therapy in solid tumors specificities [ 79 ] hurdles to chimeric antigen receptor natural killer NK! Feeder cells drive robust expansion and metabolic activation of NK cells [ 121 ], et al NK! Nkp46 + in humans ( NK ) cells inhibit systemic metastasis of glioblastoma dictates the status of NK.! A new target for CAR-NK cell immunotherapy of CD73 ( + ) solid tumors is still in development... Effector cell population equipped with fast-acting and potent anti-tumor capacity cells for targeted therapy of glioblastoma and patient-derived stem! The BiKEs or TrikEs are composed of two or three linked single-chain antibody variable fragments of different antigen specificities 79...

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