The manufacturability assessment and optimization of bispecific antibodies (bsAbs) during the discovery stage are crucial for the success of the drug development process, impacting the speed and cost of advancing such therapeutics to the Investigational New Drug (IND) stage and ultimately to the market. The complexity of bsAbs creates challenges in employing effective evaluation methods to detect developability risks in early discovery stage, and poses difficulties in identifying the root causes and implementing subsequent engineering solutions. This study presents a case of engineering a bsAb that displayed a normal solution appearance during the discovery phase but underwent significant precipitation when subjected to agitation stress during 15 L Chemistry, Manufacturing, and Control (CMC) production Leveraging analytical tools, structural analysis, in silico prediction, and wet-lab validations, the key molecular origins responsible for the observed precipitation were identified and addressed. Sequence engineering to reduce protein surface hydrophobicity and enhance conformational stability proved effective in resolving agitation-induced aggregation. The refined bsAb sequences enabled successful mass production in CMC department. The findings of this case study contribute to the understanding of the fundamental mechanism of agitation-induced aggregation and offer a potential protein engineering procedure for addressing similar issues in bsAb. Furthermore, this case study emphasizes the significance of a close partnership between Discovery and CMC teams. Integrating CMC's rigorous evaluation methods with Discovery's engineering capability can facilitate a streamlined development process for bsAb molecules.
{"title":"A case study of a bispecific antibody manufacturability assessment and optimization during discovery stage and its implications.","authors":"Shuang Wang, Weijie Zhang, Baotian Yang, Xudong Zhang, Jing Fang, Haopeng Rui, Zhijian Chen, Jijie Gu, Zhiqiang Chen, Jianqing Xu","doi":"10.1093/abt/tbae013","DOIUrl":"10.1093/abt/tbae013","url":null,"abstract":"<p><p>The manufacturability assessment and optimization of bispecific antibodies (bsAbs) during the discovery stage are crucial for the success of the drug development process, impacting the speed and cost of advancing such therapeutics to the Investigational New Drug (IND) stage and ultimately to the market. The complexity of bsAbs creates challenges in employing effective evaluation methods to detect developability risks in early discovery stage, and poses difficulties in identifying the root causes and implementing subsequent engineering solutions. This study presents a case of engineering a bsAb that displayed a normal solution appearance during the discovery phase but underwent significant precipitation when subjected to agitation stress during 15 L Chemistry, Manufacturing, and Control (CMC) production Leveraging analytical tools, structural analysis, <i>in silico</i> prediction, and wet-lab validations, the key molecular origins responsible for the observed precipitation were identified and addressed. Sequence engineering to reduce protein surface hydrophobicity and enhance conformational stability proved effective in resolving agitation-induced aggregation. The refined bsAb sequences enabled successful mass production in CMC department. The findings of this case study contribute to the understanding of the fundamental mechanism of agitation-induced aggregation and offer a potential protein engineering procedure for addressing similar issues in bsAb. Furthermore, this case study emphasizes the significance of a close partnership between Discovery and CMC teams. Integrating CMC's rigorous evaluation methods with Discovery's engineering capability can facilitate a streamlined development process for bsAb molecules.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"7 3","pages":"189-198"},"PeriodicalIF":0.0,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11259756/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141735244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yuanzhi Chen, Zhiren Zeng, Ziyou Chen, Na Yuan, Xinya Ye, Chengcheng Zhang, N. Xia, Wenxin Luo
The recent discovery of public antibodies targeting Plasmodium falciparum-encoded repetitive interspersed families of polypeptides (RIFINs), which contain extracellular immunoglobulin-like domains from LAIR1 or LILRB1, constitutes a significant step forward in comprehending the reactivity of the Plasmodium parasite. These antibodies arise from unique B cell clones and demonstrate extensive cross-reactivity through their interaction with Plasmodium falciparum RIFINs. LAIR1 and LILRBs are specialized type I transmembrane glycoproteins, classified as immune inhibitory receptors, restricted to primates and mainly found on hematopoietic cells. They are instrumental in modulating interactions within the tumor microenvironment and across the immune system, and are increasingly recognized as important in anti-cancer immunotherapy and pathogen defense. The presence of LAIR1/LILRB1-containing antibodies offers new insights into malaria parasite evasion strategies and the immune system’s response. Additionally, the innovative method of integrating extra exons into the antibody switch region is a noteworthy advancement, enriching the strategies for the generation of a varied array of bispecific and multispecific antibodies.
最近发现了针对恶性疟原虫编码的重复穿插多肽家族（RIFINs）的公共抗体，这些抗体含有来自 LAIR1 或 LILRB1 的细胞外免疫球蛋白样结构域，这是在理解疟原虫反应性方面迈出的重要一步。这些抗体来自于独特的 B 细胞克隆，并通过与恶性疟原虫 RIFINs 的相互作用表现出广泛的交叉反应性。LAIR1 和 LILRBs 是专门的 I 型跨膜糖蛋白，被归类为免疫抑制受体，仅限于灵长类动物，主要存在于造血细胞上。它们在调节肿瘤微环境和整个免疫系统的相互作用方面起着重要作用，在抗癌免疫疗法和病原体防御中的重要性日益得到认可。含有 LAIR1/LILRB1 的抗体的存在为我们提供了关于疟原虫逃避策略和免疫系统反应的新见解。此外，将额外的外显子整合到抗体开关区的创新方法也是一个值得注意的进步，它丰富了生成各种双特异性和多特异性抗体的策略。
{"title":"A new mechanism of antibody diversity: formation of the natural antibodies containing LAIR1 and LILRB1 extracellular domains","authors":"Yuanzhi Chen, Zhiren Zeng, Ziyou Chen, Na Yuan, Xinya Ye, Chengcheng Zhang, N. Xia, Wenxin Luo","doi":"10.1093/abt/tbae008","DOIUrl":"https://doi.org/10.1093/abt/tbae008","url":null,"abstract":"\u0000 The recent discovery of public antibodies targeting Plasmodium falciparum-encoded repetitive interspersed families of polypeptides (RIFINs), which contain extracellular immunoglobulin-like domains from LAIR1 or LILRB1, constitutes a significant step forward in comprehending the reactivity of the Plasmodium parasite. These antibodies arise from unique B cell clones and demonstrate extensive cross-reactivity through their interaction with Plasmodium falciparum RIFINs. LAIR1 and LILRBs are specialized type I transmembrane glycoproteins, classified as immune inhibitory receptors, restricted to primates and mainly found on hematopoietic cells. They are instrumental in modulating interactions within the tumor microenvironment and across the immune system, and are increasingly recognized as important in anti-cancer immunotherapy and pathogen defense. The presence of LAIR1/LILRB1-containing antibodies offers new insights into malaria parasite evasion strategies and the immune system’s response. Additionally, the innovative method of integrating extra exons into the antibody switch region is a noteworthy advancement, enriching the strategies for the generation of a varied array of bispecific and multispecific antibodies.","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"25 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141113760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Correction to: Role of antibody engineering in generation of derivatives starting from MOv19 MAb: 40 years of biological/therapeutic tools against folate receptor alfa","authors":"","doi":"10.1093/abt/tbae010","DOIUrl":"https://doi.org/10.1093/abt/tbae010","url":null,"abstract":"","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"51 16","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140975351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marisa L Yang, Tom Z. Yuan, Kara Y Chan, Lin Ding, Zhen Han, Hector Franco, Carson Holliday, Shruthi Kannan, E. Davidson, B. Doranz, K. Chandran, E. H. Miller, Jessica A. Plante, Scott C Weaver, Eunice Cho, Shweta Kailasan, Lukas Marsalek, Hoa Giang, Y. Abdiche, Aaron Sato
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve, escape coronavirus disease 2019 therapeutics and vaccines, and jeopardize public health. To combat SARS-CoV-2 antigenic escape, we developed a rapid, high-throughput pipeline to discover monospecific VHH antibodies and iteratively develop VHH-Fc-VHH bispecifics capable of neutralizing emerging SARS-CoV-2 variants. By panning VHH single-domain phage libraries against ancestral or Beta spike proteins, we discovered high-affinity VHH antibodies with unique target epitopes. Combining two VHHs into a tetravalent bispecific construct conferred broad neutralization activity against multiple variants and was more resistant to antigenic escape than the monospecific antibody alone. Following the rise of the Omicron variant, a VHH in the original bispecific construct was replaced with another VHH discovered against Omicron BA.1 receptor binding domain—the resulting bispecific exhibited neutralization against both BA.1 and BA.5 sublineage variants. A heavy chain-only tetravalent VHH-Fc-VHH bispecific platform derived from humanized synthetic libraries held a myriad of unique advantages: 1) synthetic preconstructed libraries minimized risk of liabilities and maximized discovery speed, 2) VHH scaffolds allowed for a modular “plug-and-play” format that could be rapidly iterated upon as variants of concern arose, 3) natural dimerization of single VHH-Fc-VHH polypeptides allowed for straightforward bispecific production and purification methods, and 4) multivalent approaches enhanced avidity boosting effects and neutralization potency, and conferred more robust resistance to antigenic escape than monovalent approaches against specific variants. This iterative platform of rapid VHH discovery combined with modular bispecific design holds promise for long-term viral control efforts.
{"title":"A VHH single-domain platform enabling discovery and development of monospecific antibodies and modular neutralizing bispecifics against SARS-CoV-2 variants","authors":"Marisa L Yang, Tom Z. Yuan, Kara Y Chan, Lin Ding, Zhen Han, Hector Franco, Carson Holliday, Shruthi Kannan, E. Davidson, B. Doranz, K. Chandran, E. H. Miller, Jessica A. Plante, Scott C Weaver, Eunice Cho, Shweta Kailasan, Lukas Marsalek, Hoa Giang, Y. Abdiche, Aaron Sato","doi":"10.1093/abt/tbae009","DOIUrl":"https://doi.org/10.1093/abt/tbae009","url":null,"abstract":"\u0000 \u0000 \u0000 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to evolve, escape coronavirus disease 2019 therapeutics and vaccines, and jeopardize public health.\u0000 \u0000 \u0000 \u0000 To combat SARS-CoV-2 antigenic escape, we developed a rapid, high-throughput pipeline to discover monospecific VHH antibodies and iteratively develop VHH-Fc-VHH bispecifics capable of neutralizing emerging SARS-CoV-2 variants.\u0000 \u0000 \u0000 \u0000 By panning VHH single-domain phage libraries against ancestral or Beta spike proteins, we discovered high-affinity VHH antibodies with unique target epitopes. Combining two VHHs into a tetravalent bispecific construct conferred broad neutralization activity against multiple variants and was more resistant to antigenic escape than the monospecific antibody alone. Following the rise of the Omicron variant, a VHH in the original bispecific construct was replaced with another VHH discovered against Omicron BA.1 receptor binding domain—the resulting bispecific exhibited neutralization against both BA.1 and BA.5 sublineage variants.\u0000 \u0000 \u0000 \u0000 A heavy chain-only tetravalent VHH-Fc-VHH bispecific platform derived from humanized synthetic libraries held a myriad of unique advantages: 1) synthetic preconstructed libraries minimized risk of liabilities and maximized discovery speed, 2) VHH scaffolds allowed for a modular “plug-and-play” format that could be rapidly iterated upon as variants of concern arose, 3) natural dimerization of single VHH-Fc-VHH polypeptides allowed for straightforward bispecific production and purification methods, and 4) multivalent approaches enhanced avidity boosting effects and neutralization potency, and conferred more robust resistance to antigenic escape than monovalent approaches against specific variants. This iterative platform of rapid VHH discovery combined with modular bispecific design holds promise for long-term viral control efforts.\u0000","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"95 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141017619","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In calendar year 2023, the United States Food and Drug Administration (US FDA) approved a total of 55 new molecular entities (NMEs), of which 12 were in the class of therapeutic antibodies. Besides antibody protein drugs, the US FDA also approved another five non-antibody protein drugs, making the broader class of protein drugs about 31% of the total approved drugs. Amongst the 12 therapeutic antibodies approved by the US FDA, eight were relatively standard IgG formats, three were bivalent, bispecific antibodies, and one was a trivalent, bispecific antibody. In 2023, no new antibody-drug conjugates, immunocytokines, or chimeric antigen receptor T (CAR-T) cells were approved. Of the approved antibodies, two targeted programmed cell death receptor (PD)-1 for orphan indications, two targeted CD20 for diffuse large B cell lymphoma (DLBCL), two different targets (B-cell maturation antigen [BCMA] and G-coupled protein receptor class C, group 5, member D [GPRC5D]) for treatment of multiple myeloma (MM), and one each that targeted amyloid-β protofibrils for Alzheimer’s disease, neonatal Fc receptor (FcRn) alpha-chain for myasthenia gravis, complement factor C5 for CD55 deficiency with Hyper-activation of complement, Angiopathic thrombosis, and severe Protein-Losing Enteropathy (CHAPLE) disease, interleukin (IL)-23p19 for severely active ulcerative colitis, IL-17A-F for plaque psoriasis, and respiratory syncytial virus (RSV)-F protein for season-long RSV prophylaxis in infants.
{"title":"Structure and function of therapeutic antibodies approved by the US FDA in 2023","authors":"William R Strohl","doi":"10.1093/abt/tbae007","DOIUrl":"https://doi.org/10.1093/abt/tbae007","url":null,"abstract":"\u0000 In calendar year 2023, the United States Food and Drug Administration (US FDA) approved a total of 55 new molecular entities (NMEs), of which 12 were in the class of therapeutic antibodies. Besides antibody protein drugs, the US FDA also approved another five non-antibody protein drugs, making the broader class of protein drugs about 31% of the total approved drugs. Amongst the 12 therapeutic antibodies approved by the US FDA, eight were relatively standard IgG formats, three were bivalent, bispecific antibodies, and one was a trivalent, bispecific antibody. In 2023, no new antibody-drug conjugates, immunocytokines, or chimeric antigen receptor T (CAR-T) cells were approved. Of the approved antibodies, two targeted programmed cell death receptor (PD)-1 for orphan indications, two targeted CD20 for diffuse large B cell lymphoma (DLBCL), two different targets (B-cell maturation antigen [BCMA] and G-coupled protein receptor class C, group 5, member D [GPRC5D]) for treatment of multiple myeloma (MM), and one each that targeted amyloid-β protofibrils for Alzheimer’s disease, neonatal Fc receptor (FcRn) alpha-chain for myasthenia gravis, complement factor C5 for CD55 deficiency with Hyper-activation of complement, Angiopathic thrombosis, and severe Protein-Losing Enteropathy (CHAPLE) disease, interleukin (IL)-23p19 for severely active ulcerative colitis, IL-17A-F for plaque psoriasis, and respiratory syncytial virus (RSV)-F protein for season-long RSV prophylaxis in infants.","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"74 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140229908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiaolei Liu, Jianzhong Han, Qian Wang, Peng Wang, Li Li, Kehe Du, Fengchao Jiang, Pei Zhang, Hongjun Liu, Jian Huang
Abstract Thymic stromal lymphopoietin (TSLP) is a member of the IL-2 cytokine family and has been widely recognized as a master regulator of type 2 inflammatory responses at barrier surfaces. Recent studies found dysregulation of the TSLP–TSLP receptor (TSLPR) pathway is associated with the pathogenesis of not only allergic diseases but also a wide variety of cancers including both solid tumors and hematological tumors. Thus, the blockade of TSLP represents an attractive therapeutic strategy for allergic diseases and cancer. In this study, we report the development of a novel humanized anti-TSLP monoclonal antibody (mAb) HZ-1127. Binding affinity, specificity, and ability of HZ-1127 in inhibiting TSLP were tested. HZ-1127 selectively binds to the TSLP cytokine with high affinity and specificity. Furthermore, HZ-1127 dramatically inhibits TSLP-dependent STAT5 activation and is more potent than Tezepelumab, which is an FDA-approved humanized mAb against TSLP for severe asthma treatment in inhibiting TSLP-induced CCL17 and CCL22 chemokines secretion in human peripheral blood mononuclear cells. Our pre-clinical study demonstrates that HZ-1127 may serve as a potential therapeutic agent for allergic diseases and cancer.
{"title":"Development of a novel humanized anti-TSLP monoclonal antibody HZ-1127 with anti-allergic diseases and cancer potential","authors":"Xiaolei Liu, Jianzhong Han, Qian Wang, Peng Wang, Li Li, Kehe Du, Fengchao Jiang, Pei Zhang, Hongjun Liu, Jian Huang","doi":"10.1093/abt/tbae006","DOIUrl":"https://doi.org/10.1093/abt/tbae006","url":null,"abstract":"Abstract Thymic stromal lymphopoietin (TSLP) is a member of the IL-2 cytokine family and has been widely recognized as a master regulator of type 2 inflammatory responses at barrier surfaces. Recent studies found dysregulation of the TSLP–TSLP receptor (TSLPR) pathway is associated with the pathogenesis of not only allergic diseases but also a wide variety of cancers including both solid tumors and hematological tumors. Thus, the blockade of TSLP represents an attractive therapeutic strategy for allergic diseases and cancer. In this study, we report the development of a novel humanized anti-TSLP monoclonal antibody (mAb) HZ-1127. Binding affinity, specificity, and ability of HZ-1127 in inhibiting TSLP were tested. HZ-1127 selectively binds to the TSLP cytokine with high affinity and specificity. Furthermore, HZ-1127 dramatically inhibits TSLP-dependent STAT5 activation and is more potent than Tezepelumab, which is an FDA-approved humanized mAb against TSLP for severe asthma treatment in inhibiting TSLP-induced CCL17 and CCL22 chemokines secretion in human peripheral blood mononuclear cells. Our pre-clinical study demonstrates that HZ-1127 may serve as a potential therapeutic agent for allergic diseases and cancer.","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"55 9","pages":"123 - 130"},"PeriodicalIF":0.0,"publicationDate":"2024-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140425694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Abstract In recent years, substantial therapeutic efficacy of antibody-drug conjugates (ADCs) has been validated through approvals of 16 ADCs for the treatment of malignant tumors. However, realization of the maximum clinical use of ADCs requires surmounting extant challenges, mainly the limitations in tumor penetration capabilities when targeting solid tumors. To resolve the hurdle of suboptimal tumor penetration, miniaturized antibody fragments with engineered formats have been harnessed for ADC assembly. By virtue of their reduced molecular sizes, antibody fragment-drug conjugates hold considerable promise for efficacious delivery of cytotoxic agents, thus conferring superior therapeutic outcomes. This review will focus on current advancements in novel ADC development utilizing smaller antibody formats from ~6 to 80 kDa, with particular emphasis on single-domain antibodies, which have been widely applied in novel ADC design. Additionally, strategies to optimize clinical translation are discussed, including half-life extension, acceleration of internalization, and reduction of immunogenic potential.
{"title":"Reforming solid tumor treatment: the emerging potential of smaller format antibody-drug conjugate","authors":"Xiaojie Ma, Mingkai Wang, Tianlei Ying, Yan-ling Wu","doi":"10.1093/abt/tbae005","DOIUrl":"https://doi.org/10.1093/abt/tbae005","url":null,"abstract":"Abstract In recent years, substantial therapeutic efficacy of antibody-drug conjugates (ADCs) has been validated through approvals of 16 ADCs for the treatment of malignant tumors. However, realization of the maximum clinical use of ADCs requires surmounting extant challenges, mainly the limitations in tumor penetration capabilities when targeting solid tumors. To resolve the hurdle of suboptimal tumor penetration, miniaturized antibody fragments with engineered formats have been harnessed for ADC assembly. By virtue of their reduced molecular sizes, antibody fragment-drug conjugates hold considerable promise for efficacious delivery of cytotoxic agents, thus conferring superior therapeutic outcomes. This review will focus on current advancements in novel ADC development utilizing smaller antibody formats from ~6 to 80 kDa, with particular emphasis on single-domain antibodies, which have been widely applied in novel ADC design. Additionally, strategies to optimize clinical translation are discussed, including half-life extension, acceleration of internalization, and reduction of immunogenic potential.","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"310 1","pages":"114 - 122"},"PeriodicalIF":0.0,"publicationDate":"2024-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140453684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Correction to: Bringing cell therapy to tumors: considerations for optimal CAR binder design","authors":"","doi":"10.1093/abt/tbae003","DOIUrl":"https://doi.org/10.1093/abt/tbae003","url":null,"abstract":"","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"76 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139963975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anhye Kim, Min-Seok Oh, Gwan-Ho Lee, Seongeun Song, Mi-sun Byun, Donghoon Choi, Byung-Yong Yu, Howard Lee
Antibody-based therapeutics (ABTs) including monoclonal/polyclonal antibodies and Fc-fusion proteins are increasingly used in disease treatment, driving the global market growth. Understanding the pharmacokinetic (PK) properties of ABTs is crucial for their clinical effectiveness. This study investigated the PK profile and tissue distribution of efineptakin alfa, a long-acting recombinant human interleukin-7 (rhIL-7-hyFc), using enzyme-linked immunosorbent assay (ELISA) and accelerator mass spectrometry (AMS). Total 4 rats were injected intramuscularly with 1 mg/kg of rhIL-7-hyFc containing 14C-rhIL-7-hyFc, prepared via reductive methylation. Serum total radioactivity (TRA) and serum rhIL-7-hyFc concentrations were quantified using AMS and ELISA, respectively. TRA concentrations in organs were determined by AMS. Serum TRA peaked at 10 hours with a terminal half-life of 40 hours. rhIL-7-hyFc exhibited a mean peak concentration at around 17 hours and a rapid elimination with a half-life of 12.3 hours. Peak concentration and area under the curve of TRA were higher than those of rhIL-7-hyFc. Tissue distribution analysis showed elevated TRA concentrations in lymph nodes, kidneys, and spleen, indicating rhIL-7-hyFc’s affinity for these organs. The study also simulated the positions of 14C labeling in rhIL-7-hyFc, identifying specific residues in the fragment of rhIL-7 portion, and provided the explanation of distinct analytes targeted by each method. Combining ELISA and AMS provided advantages by offering sensitivity and specificity for quantification, as well as enabling the identification of analyte forms. The integrated use of ELISA and AMS offer valuable insights for the development and optimization of ABT.
{"title":"Understanding the pharmacokinetic journey of fc-fusion protein, rhIL-7-hyFc, using complementary approach of two analytical methods, accelerator mass spectrometry and ELISA","authors":"Anhye Kim, Min-Seok Oh, Gwan-Ho Lee, Seongeun Song, Mi-sun Byun, Donghoon Choi, Byung-Yong Yu, Howard Lee","doi":"10.1093/abt/tbae004","DOIUrl":"https://doi.org/10.1093/abt/tbae004","url":null,"abstract":"\u0000 \u0000 \u0000 Antibody-based therapeutics (ABTs) including monoclonal/polyclonal antibodies and Fc-fusion proteins are increasingly used in disease treatment, driving the global market growth. Understanding the pharmacokinetic (PK) properties of ABTs is crucial for their clinical effectiveness. This study investigated the PK profile and tissue distribution of efineptakin alfa, a long-acting recombinant human interleukin-7 (rhIL-7-hyFc), using enzyme-linked immunosorbent assay (ELISA) and accelerator mass spectrometry (AMS).\u0000 \u0000 \u0000 \u0000 Total 4 rats were injected intramuscularly with 1 mg/kg of rhIL-7-hyFc containing 14C-rhIL-7-hyFc, prepared via reductive methylation. Serum total radioactivity (TRA) and serum rhIL-7-hyFc concentrations were quantified using AMS and ELISA, respectively. TRA concentrations in organs were determined by AMS.\u0000 \u0000 \u0000 \u0000 Serum TRA peaked at 10 hours with a terminal half-life of 40 hours. rhIL-7-hyFc exhibited a mean peak concentration at around 17 hours and a rapid elimination with a half-life of 12.3 hours. Peak concentration and area under the curve of TRA were higher than those of rhIL-7-hyFc. Tissue distribution analysis showed elevated TRA concentrations in lymph nodes, kidneys, and spleen, indicating rhIL-7-hyFc’s affinity for these organs. The study also simulated the positions of 14C labeling in rhIL-7-hyFc, identifying specific residues in the fragment of rhIL-7 portion, and provided the explanation of distinct analytes targeted by each method.\u0000 \u0000 \u0000 \u0000 Combining ELISA and AMS provided advantages by offering sensitivity and specificity for quantification, as well as enabling the identification of analyte forms. The integrated use of ELISA and AMS offer valuable insights for the development and optimization of ABT.\u0000","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"4 7","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139800525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anhye Kim, Min-Seok Oh, Gwan-Ho Lee, Seongeun Song, Mi-sun Byun, Donghoon Choi, Byung-Yong Yu, Howard Lee
Antibody-based therapeutics (ABTs) including monoclonal/polyclonal antibodies and Fc-fusion proteins are increasingly used in disease treatment, driving the global market growth. Understanding the pharmacokinetic (PK) properties of ABTs is crucial for their clinical effectiveness. This study investigated the PK profile and tissue distribution of efineptakin alfa, a long-acting recombinant human interleukin-7 (rhIL-7-hyFc), using enzyme-linked immunosorbent assay (ELISA) and accelerator mass spectrometry (AMS). Total 4 rats were injected intramuscularly with 1 mg/kg of rhIL-7-hyFc containing 14C-rhIL-7-hyFc, prepared via reductive methylation. Serum total radioactivity (TRA) and serum rhIL-7-hyFc concentrations were quantified using AMS and ELISA, respectively. TRA concentrations in organs were determined by AMS. Serum TRA peaked at 10 hours with a terminal half-life of 40 hours. rhIL-7-hyFc exhibited a mean peak concentration at around 17 hours and a rapid elimination with a half-life of 12.3 hours. Peak concentration and area under the curve of TRA were higher than those of rhIL-7-hyFc. Tissue distribution analysis showed elevated TRA concentrations in lymph nodes, kidneys, and spleen, indicating rhIL-7-hyFc’s affinity for these organs. The study also simulated the positions of 14C labeling in rhIL-7-hyFc, identifying specific residues in the fragment of rhIL-7 portion, and provided the explanation of distinct analytes targeted by each method. Combining ELISA and AMS provided advantages by offering sensitivity and specificity for quantification, as well as enabling the identification of analyte forms. The integrated use of ELISA and AMS offer valuable insights for the development and optimization of ABT.
{"title":"Understanding the pharmacokinetic journey of fc-fusion protein, rhIL-7-hyFc, using complementary approach of two analytical methods, accelerator mass spectrometry and ELISA","authors":"Anhye Kim, Min-Seok Oh, Gwan-Ho Lee, Seongeun Song, Mi-sun Byun, Donghoon Choi, Byung-Yong Yu, Howard Lee","doi":"10.1093/abt/tbae004","DOIUrl":"https://doi.org/10.1093/abt/tbae004","url":null,"abstract":"\u0000 \u0000 \u0000 Antibody-based therapeutics (ABTs) including monoclonal/polyclonal antibodies and Fc-fusion proteins are increasingly used in disease treatment, driving the global market growth. Understanding the pharmacokinetic (PK) properties of ABTs is crucial for their clinical effectiveness. This study investigated the PK profile and tissue distribution of efineptakin alfa, a long-acting recombinant human interleukin-7 (rhIL-7-hyFc), using enzyme-linked immunosorbent assay (ELISA) and accelerator mass spectrometry (AMS).\u0000 \u0000 \u0000 \u0000 Total 4 rats were injected intramuscularly with 1 mg/kg of rhIL-7-hyFc containing 14C-rhIL-7-hyFc, prepared via reductive methylation. Serum total radioactivity (TRA) and serum rhIL-7-hyFc concentrations were quantified using AMS and ELISA, respectively. TRA concentrations in organs were determined by AMS.\u0000 \u0000 \u0000 \u0000 Serum TRA peaked at 10 hours with a terminal half-life of 40 hours. rhIL-7-hyFc exhibited a mean peak concentration at around 17 hours and a rapid elimination with a half-life of 12.3 hours. Peak concentration and area under the curve of TRA were higher than those of rhIL-7-hyFc. Tissue distribution analysis showed elevated TRA concentrations in lymph nodes, kidneys, and spleen, indicating rhIL-7-hyFc’s affinity for these organs. The study also simulated the positions of 14C labeling in rhIL-7-hyFc, identifying specific residues in the fragment of rhIL-7 portion, and provided the explanation of distinct analytes targeted by each method.\u0000 \u0000 \u0000 \u0000 Combining ELISA and AMS provided advantages by offering sensitivity and specificity for quantification, as well as enabling the identification of analyte forms. The integrated use of ELISA and AMS offer valuable insights for the development and optimization of ABT.\u0000","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"61 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139860662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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