Pub Date : 2024-01-01Epub Date: 2024-08-27DOI: 10.1080/19420862.2024.2394229
Alaa Amash, Gesa Volkers, Patrick Farber, Daniel Griffin, K Shawn Davison, Allison Goodman, Raffi Tonikian, Aaron Yamniuk, Bryan Barnhart, Tim Jacobs
Bispecific antibodies (bsAb) and multispecific antibodies (msAb) encompass a diverse variety of formats that can concurrently bind multiple epitopes, unlocking mechanisms to address previously difficult-to-treat or incurable diseases. Early assessment of candidate developability enables demotion of antibodies with low potential and promotion of the most promising candidates for further development. Protein-based therapies have a stringent set of developability requirements in order to be competitive (e.g. high-concentration formulation, and long half-life) and their assessment requires a robust toolkit of methods, few of which are validated for interrogating bsAbs/msAbs. Important considerations when assessing the developability of bsAbs/msAbs include their molecular format, likelihood for immunogenicity, specificity, stability, and potential for high-volume production. Here, we summarize the critical aspects of developability assessment, and provide guidance on how to develop a comprehensive plan tailored to a given bsAb/msAb.
{"title":"Developability considerations for bispecific and multispecific antibodies.","authors":"Alaa Amash, Gesa Volkers, Patrick Farber, Daniel Griffin, K Shawn Davison, Allison Goodman, Raffi Tonikian, Aaron Yamniuk, Bryan Barnhart, Tim Jacobs","doi":"10.1080/19420862.2024.2394229","DOIUrl":"10.1080/19420862.2024.2394229","url":null,"abstract":"<p><p>Bispecific antibodies (bsAb) and multispecific antibodies (msAb) encompass a diverse variety of formats that can concurrently bind multiple epitopes, unlocking mechanisms to address previously difficult-to-treat or incurable diseases. Early assessment of candidate developability enables demotion of antibodies with low potential and promotion of the most promising candidates for further development. Protein-based therapies have a stringent set of developability requirements in order to be competitive (e.g. high-concentration formulation, and long half-life) and their assessment requires a robust toolkit of methods, few of which are validated for interrogating bsAbs/msAbs. Important considerations when assessing the developability of bsAbs/msAbs include their molecular format, likelihood for immunogenicity, specificity, stability, and potential for high-volume production. Here, we summarize the critical aspects of developability assessment, and provide guidance on how to develop a comprehensive plan tailored to a given bsAb/msAb.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":null,"pages":null},"PeriodicalIF":5.6,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11352713/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142073235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-14DOI: 10.1080/19420862.2023.2292305
Yuqi Wang, Quan Quan, Camille Gleason, Helin Yu, Lujia Peng, Yanshen Kang, Ling Jiang, Kailun Wu, Jie Pan, Moxiyele Bao, Qing Zhu, Meiqi Yi, Ming Fang, Yue Zheng, Ling Qiu, Bin Xu, Xiang Li, Jinfeng Song, Jiamu Sun, Zheng Zhang, Zijun Su, Jara Lin, Yuanyuan Xie, April Xu, Xiling Song, Chichi Huang, Zhirong Shen, Lai Wang, Jing Song
Pharmaceutical companies have recently focused on accelerating the timeline for initiating first-in-human (FIH) trials to allow quick assessment of biologic drugs. For example, a stable cell pool c...
制药公司最近专注于加快启动首次人体试验(FIH)的时间表,以便对生物药物进行快速评估。例如,一个稳定的cell pool c…
{"title":"Accelerating the speed of innovative anti-tumor drugs to first-in-human trials incorporating key de-risk strategies","authors":"Yuqi Wang, Quan Quan, Camille Gleason, Helin Yu, Lujia Peng, Yanshen Kang, Ling Jiang, Kailun Wu, Jie Pan, Moxiyele Bao, Qing Zhu, Meiqi Yi, Ming Fang, Yue Zheng, Ling Qiu, Bin Xu, Xiang Li, Jinfeng Song, Jiamu Sun, Zheng Zhang, Zijun Su, Jara Lin, Yuanyuan Xie, April Xu, Xiling Song, Chichi Huang, Zhirong Shen, Lai Wang, Jing Song","doi":"10.1080/19420862.2023.2292305","DOIUrl":"https://doi.org/10.1080/19420862.2023.2292305","url":null,"abstract":"Pharmaceutical companies have recently focused on accelerating the timeline for initiating first-in-human (FIH) trials to allow quick assessment of biologic drugs. For example, a stable cell pool c...","PeriodicalId":18206,"journal":{"name":"mAbs","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2023-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138629894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-13DOI: 10.1080/19420862.2023.2291209
M. Frank Erasmus, Molly Dovner, Fortunato Ferrara, Sara D’Angelo, André A. Teixeira, Camila Leal-Lopes, Laura Spector, Elizabeth Hopkins, Andrew R. M. Bradbury
Accurate and efficient affinity measurement techniques are essential for the biophysical characterization of therapeutic monoclonal antibodies, one of the fastest growing drug classes. Surface plas...
{"title":"Determining the affinities of high-affinity antibodies using KinExA and surface plasmon resonance","authors":"M. Frank Erasmus, Molly Dovner, Fortunato Ferrara, Sara D’Angelo, André A. Teixeira, Camila Leal-Lopes, Laura Spector, Elizabeth Hopkins, Andrew R. M. Bradbury","doi":"10.1080/19420862.2023.2291209","DOIUrl":"https://doi.org/10.1080/19420862.2023.2291209","url":null,"abstract":"Accurate and efficient affinity measurement techniques are essential for the biophysical characterization of therapeutic monoclonal antibodies, one of the fastest growing drug classes. Surface plas...","PeriodicalId":18206,"journal":{"name":"mAbs","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2023-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138630081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-12DOI: 10.1080/19420862.2023.2289681
Gareth C. G. Davies, Neesha Dedi, Paul S. Jones, Lara Kevorkian, David McMillan, Cristina Ottone, Monika-Sarah E. D. Schulze, Anthony Scott-Tucker, Roohi Tewari, Shauna West, Michael Wright, Tania F. Rowley
Gremlin-1, a high-affinity antagonist of bone morphogenetic proteins (BMP)-2, −4, and −7, is implicated in tumor initiation and progression. Increased gremlin-1 expression, and therefore suppressed...
{"title":"Discovery of ginisortamab, a potent and novel anti-gremlin-1 antibody in clinical development for the treatment of cancer","authors":"Gareth C. G. Davies, Neesha Dedi, Paul S. Jones, Lara Kevorkian, David McMillan, Cristina Ottone, Monika-Sarah E. D. Schulze, Anthony Scott-Tucker, Roohi Tewari, Shauna West, Michael Wright, Tania F. Rowley","doi":"10.1080/19420862.2023.2289681","DOIUrl":"https://doi.org/10.1080/19420862.2023.2289681","url":null,"abstract":"Gremlin-1, a high-affinity antagonist of bone morphogenetic proteins (BMP)-2, −4, and −7, is implicated in tumor initiation and progression. Increased gremlin-1 expression, and therefore suppressed...","PeriodicalId":18206,"journal":{"name":"mAbs","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2023-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138573911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-04-05DOI: 10.48550/arXiv.2304.02258
M. Los, Z. Christoff, D. Grossi
The popularity of an opinion in one's direct circles is not necessarily a good indicator of its popularity in one's entire community. For instance, when confronted with a majority of opposing opinions in one's circles, one might get the impression that one belongs to a minority. From this perspective, network structure makes local information about global properties of the group potentially inaccurate. However, the way a social network is wired also determines what kind of information distortion can actually occur. In this paper, we discuss which classes of networks allow for a majority of agents to have the wrong impression about what the majority opinion is, that is, to be in a 'majority illusion'.
{"title":"On the graph theory of majority illusions","authors":"M. Los, Z. Christoff, D. Grossi","doi":"10.48550/arXiv.2304.02258","DOIUrl":"https://doi.org/10.48550/arXiv.2304.02258","url":null,"abstract":"The popularity of an opinion in one's direct circles is not necessarily a good indicator of its popularity in one's entire community. For instance, when confronted with a majority of opposing opinions in one's circles, one might get the impression that one belongs to a minority. From this perspective, network structure makes local information about global properties of the group potentially inaccurate. However, the way a social network is wired also determines what kind of information distortion can actually occur. In this paper, we discuss which classes of networks allow for a majority of agents to have the wrong impression about what the majority opinion is, that is, to be in a 'majority illusion'.","PeriodicalId":18206,"journal":{"name":"mAbs","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2023-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72895932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-01DOI: 10.1080/19420862.2023.2175312
Dario A T Cramer, Vojtech Franc, Anna-Katharina Heidenreich, Michaela Hook, Mahdi Adibzadeh, Dietmar Reusch, Albert J R Heck, Markus Haberger
The development of increasingly complex antibody formats, such as bispecifics, can lead to the formation of increasingly complex high- and low-molecular-weight by-products. Here, we focus on the characterization of high molecular weight species (HMWs) representing the highest complexity of size variants. Standard methods used for product release, such as size exclusion chromatography (SEC), can separate HMW by-products from the main product, but cannot distinguish smaller changes in mass. Here, for the identification of the diverse and complex HMW variants of a trivalent bispecific CrossMAb antibody, offline fractionation, as well as production of HMW by-products combined with comprehensive analytical testing, was applied. Furthermore, HMW variants were analyzed regarding their chemical binding nature and tested in functional assays regarding changes in potency of the variants. Changes in potency were explained by detailed characterization using mass photometry, SDS-PAGE analysis, native mass spectrometry (MS) coupled to SEC and bottom-up proteomics. We identified a major portion of the HMW by-products to be non-covalently linked, leading to dissociation and changes in activity. We also identified and localized high heterogeneity of a by-product of concern and applied a CD3 affinity column coupled to native MS to annotate unexpected by-products. We present here a multi-method approach for the characterization of complex HMW by-products. A better understanding of these by-products is beneficial to guide analytical method development and proper specification setting for therapeutic bispecific antibodies to ensure constant efficacy and patient safety of the product through the assessment of by-products.
{"title":"Characterization of high-molecular weight by-products in the production of a trivalent bispecific 2+1 heterodimeric antibody.","authors":"Dario A T Cramer, Vojtech Franc, Anna-Katharina Heidenreich, Michaela Hook, Mahdi Adibzadeh, Dietmar Reusch, Albert J R Heck, Markus Haberger","doi":"10.1080/19420862.2023.2175312","DOIUrl":"https://doi.org/10.1080/19420862.2023.2175312","url":null,"abstract":"<p><p>The development of increasingly complex antibody formats, such as bispecifics, can lead to the formation of increasingly complex high- and low-molecular-weight by-products. Here, we focus on the characterization of high molecular weight species (HMWs) representing the highest complexity of size variants. Standard methods used for product release, such as size exclusion chromatography (SEC), can separate HMW by-products from the main product, but cannot distinguish smaller changes in mass. Here, for the identification of the diverse and complex HMW variants of a trivalent bispecific CrossMAb antibody, offline fractionation, as well as production of HMW by-products combined with comprehensive analytical testing, was applied. Furthermore, HMW variants were analyzed regarding their chemical binding nature and tested in functional assays regarding changes in potency of the variants. Changes in potency were explained by detailed characterization using mass photometry, SDS-PAGE analysis, native mass spectrometry (MS) coupled to SEC and bottom-up proteomics. We identified a major portion of the HMW by-products to be non-covalently linked, leading to dissociation and changes in activity. We also identified and localized high heterogeneity of a by-product of concern and applied a CD3 affinity column coupled to native MS to annotate unexpected by-products. We present here a multi-method approach for the characterization of complex HMW by-products. A better understanding of these by-products is beneficial to guide analytical method development and proper specification setting for therapeutic bispecific antibodies to ensure constant efficacy and patient safety of the product through the assessment of by-products.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9980510/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9128694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
We designed and developed a novel DNA topoisomerase I inhibitor MF-6, which was a more potent cytotoxin and a more potent inducer of immunogenic cell death compared with DXd. To utilize MF-6's ability to induce antitumor immunity, a human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate (ADC) trastuzumab-L6 that included a cleavable linker and MF-6 was developed. Different from traditional cytotoxic ADC, the antitumor activity of trastuzumab-L6 was assessed by inducing tumor cell immunogenic cell death, activating dendritic cells and cytotoxic CD8+ T cells to acquire durable adaptive immune memory. Tumor cells treated with trastuzumab-L6 were committed to immunogenic cell death, with upregulation of damage-associated molecular patterns and antigen presentation molecules. In a syngeneic tumor model with a mouse cell line that expressed human HER2, immunocompetent mice showed greater antitumor efficacy compared with nude mice. The trastuzumab-L6-cured immunocompetent mice acquired adaptive antitumor memory and rejected subsequent tumor cell challenge. The trastuzumab-L6 efficacy was abrogated when cytotoxic CD8+ T cells were depleted and enhanced when regulatory CD4+ T cells were depleted. The combination of trastuzumab-L6 with immune checkpoint inhibitors significantly increased antitumor efficacy. Enhanced T cell infiltration, dendritic cell activation, and decreased type M2 macrophages in tumor post trastuzumab-L6 administration confirmed the immune-activating responses. In conclusion, trastuzumab-L6 was considered to be an immunostimulatory agent, rather than a traditional cytotoxic ADC, and its antitumor efficacy was enhanced when combined with an anti-PD-L1 and anti-CTLA-4 antibody, which suggested a potential therapeutic strategy.
{"title":"A HER2-targeted antibody-novel DNA topoisomerase I inhibitor conjugate induces durable adaptive antitumor immunity by activating dendritic cells.","authors":"Xiaoding Tan, Peng Fang, Kaiying Li, Meng You, Yuxia Cao, Hui Xu, Xiaohong Zhu, Lu Wang, Xin Wei, Haiying Wen, Wendi Li, Lei Shi, Xiaowei Sun, Dongan Yu, Huikai Zhu, Zhenzhen Wang, Datao Liu, Hui Shen, Wei Zhou, Maomao An","doi":"10.1080/19420862.2023.2220466","DOIUrl":"https://doi.org/10.1080/19420862.2023.2220466","url":null,"abstract":"<p><p>We designed and developed a novel DNA topoisomerase I inhibitor MF-6, which was a more potent cytotoxin and a more potent inducer of immunogenic cell death compared with DXd. To utilize MF-6's ability to induce antitumor immunity, a human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate (ADC) trastuzumab-L6 that included a cleavable linker and MF-6 was developed. Different from traditional cytotoxic ADC, the antitumor activity of trastuzumab-L6 was assessed by inducing tumor cell immunogenic cell death, activating dendritic cells and cytotoxic CD8+ T cells to acquire durable adaptive immune memory. Tumor cells treated with trastuzumab-L6 were committed to immunogenic cell death, with upregulation of damage-associated molecular patterns and antigen presentation molecules. In a syngeneic tumor model with a mouse cell line that expressed human HER2, immunocompetent mice showed greater antitumor efficacy compared with nude mice. The trastuzumab-L6-cured immunocompetent mice acquired adaptive antitumor memory and rejected subsequent tumor cell challenge. The trastuzumab-L6 efficacy was abrogated when cytotoxic CD8+ T cells were depleted and enhanced when regulatory CD4+ T cells were depleted. The combination of trastuzumab-L6 with immune checkpoint inhibitors significantly increased antitumor efficacy. Enhanced T cell infiltration, dendritic cell activation, and decreased type M2 macrophages in tumor post trastuzumab-L6 administration confirmed the immune-activating responses. In conclusion, trastuzumab-L6 was considered to be an immunostimulatory agent, rather than a traditional cytotoxic ADC, and its antitumor efficacy was enhanced when combined with an anti-PD-L1 and anti-CTLA-4 antibody, which suggested a potential therapeutic strategy.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/cd/b0/KMAB_15_2220466.PMC10269389.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9685109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-01DOI: 10.1080/19420862.2023.2231129
Han Ping Loh, Farouq Bin Mahfut, Serene W Chen, Yuhan Huang, Jianxin Huo, Wei Zhang, Kong Peng Lam, Shengli Xu, Yuansheng Yang
T-cell-engaging bispecific antibodies (T-bsAbs) are promising immunotherapies for cancer treatment due to their capability of redirecting T-cells toward destroying tumor cells. Numerous T-bsAb formats have been developed, each with advantages and disadvantages in terms of developability, immunogenicity, effector functions, and pharmacokinetics. Here, we systematically compared T-bsAbs produced using eight different formats, evaluating the effect of molecular design of T-bsAbs on their manufacturability and functionality. These eight T-bsAb formats were constructed using antigen-binding fragments (Fabs) and single-chain variable fragments (scFvs) of antibodies linked to the crystallizable fragment (Fc) domain of immunoglobulin G. To ensure a fair comparison of growth and production data, we used recombinase-mediated cassette exchange technology to generate the T-bsAb-producing CHO cell lines. The produced T-bsAbs were assessed for their purification profile and recovery, binding capability, and biological activities. Our findings indicated that the manufacturability of bsAbs was adversely affected with increased number of scFv building blocks, while the functionality was affected by the combination of multiple factors, including the binding affinity and avidity of targeting moieties and the flexibility and geometry of formats. These results provide valuable insights into the impact of the format design on the optimal production and function of T-bsAbs.
{"title":"Manufacturability and functionality assessment of different formats of T-cell engaging bispecific antibodies.","authors":"Han Ping Loh, Farouq Bin Mahfut, Serene W Chen, Yuhan Huang, Jianxin Huo, Wei Zhang, Kong Peng Lam, Shengli Xu, Yuansheng Yang","doi":"10.1080/19420862.2023.2231129","DOIUrl":"https://doi.org/10.1080/19420862.2023.2231129","url":null,"abstract":"<p><p>T-cell-engaging bispecific antibodies (T-bsAbs) are promising immunotherapies for cancer treatment due to their capability of redirecting T-cells toward destroying tumor cells. Numerous T-bsAb formats have been developed, each with advantages and disadvantages in terms of developability, immunogenicity, effector functions, and pharmacokinetics. Here, we systematically compared T-bsAbs produced using eight different formats, evaluating the effect of molecular design of T-bsAbs on their manufacturability and functionality. These eight T-bsAb formats were constructed using antigen-binding fragments (Fabs) and single-chain variable fragments (scFvs) of antibodies linked to the crystallizable fragment (Fc) domain of immunoglobulin G. To ensure a fair comparison of growth and production data, we used recombinase-mediated cassette exchange technology to generate the T-bsAb-producing CHO cell lines. The produced T-bsAbs were assessed for their purification profile and recovery, binding capability, and biological activities. Our findings indicated that the manufacturability of bsAbs was adversely affected with increased number of scFv building blocks, while the functionality was affected by the combination of multiple factors, including the binding affinity and avidity of targeting moieties and the flexibility and geometry of formats. These results provide valuable insights into the impact of the format design on the optimal production and function of T-bsAbs.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/49/25/KMAB_15_2231129.PMC10324450.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10159470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-01-01DOI: 10.1080/19420862.2023.2254676
Stephanie Maciuba, Gregory D Bowden, Harrison J Stratton, Kazimierz Wisniewski, Claudio D Schteingart, Juan C Almagro, Philippe Valadon, Joshua Lowitz, Scott M Glaser, Grace Lee, Mahdi Dolatyari, Edita Navratilova, Frank Porreca, Pierre J M Rivière
Prolactin (PRL) has recently been demonstrated to elicit female-selective nociceptor sensitization and increase pain-like behaviors in female animals. Here we report the discovery and characterization of first-in-class, humanized PRL neutralizing monoclonal antibodies (PRL mAbs). We obtained two potent and selective PRL mAbs, PL 200,031 and PL 200,039. PL 200,031 was engineered as human IgG1 whereas PL 200,039 was reformatted as human IgG4. Both mAbs have sub-nanomolar affinity for human PRL (hPRL) and produce concentration-dependent and complete inhibition of hPRL signaling at the hPRL receptor (hPRLR). These two PRL mAbs are selective for hPRL as they do not inhibit other hPRLR agonists such as human growth hormone or placental lactogen. They also cross-react with non-human primate PRL but not with rodent PRL. Further, both mAbs show long clearance half-lives after intravenous administration in FcRn-humanized mice. Consistent with their isotypes, these mAbs only differ in binding affinities to Fcγ receptors, as expected by design. Finally, PL 200,019, the murine parental mAb of PL 200,031 and PL 200,039, fully blocked stress-induced and PRL-dependent pain behaviors in female PRL-humanized mice, thereby providing in vivo preclinical proof-of-efficacy for PRL mAbs in mechanisms relevant to pain in females.
{"title":"Discovery and characterization of prolactin neutralizing monoclonal antibodies for the treatment of female-prevalent pain disorders.","authors":"Stephanie Maciuba, Gregory D Bowden, Harrison J Stratton, Kazimierz Wisniewski, Claudio D Schteingart, Juan C Almagro, Philippe Valadon, Joshua Lowitz, Scott M Glaser, Grace Lee, Mahdi Dolatyari, Edita Navratilova, Frank Porreca, Pierre J M Rivière","doi":"10.1080/19420862.2023.2254676","DOIUrl":"10.1080/19420862.2023.2254676","url":null,"abstract":"<p><p>Prolactin (PRL) has recently been demonstrated to elicit female-selective nociceptor sensitization and increase pain-like behaviors in female animals. Here we report the discovery and characterization of first-in-class, humanized PRL neutralizing monoclonal antibodies (PRL mAbs). We obtained two potent and selective PRL mAbs, PL 200,031 and PL 200,039. PL 200,031 was engineered as human IgG1 whereas PL 200,039 was reformatted as human IgG4. Both mAbs have sub-nanomolar affinity for human PRL (hPRL) and produce concentration-dependent and complete inhibition of hPRL signaling at the hPRL receptor (hPRLR). These two PRL mAbs are selective for hPRL as they do not inhibit other hPRLR agonists such as human growth hormone or placental lactogen. They also cross-react with non-human primate PRL but not with rodent PRL. Further, both mAbs show long clearance half-lives after intravenous administration in FcRn-humanized mice. Consistent with their isotypes, these mAbs only differ in binding affinities to Fcγ receptors, as expected by design. Finally, PL 200,019, the murine parental mAb of PL 200,031 and PL 200,039, fully blocked stress-induced and PRL-dependent pain behaviors in female PRL-humanized mice, thereby providing <i>in vivo</i> preclinical proof-of-efficacy for PRL mAbs in mechanisms relevant to pain in females.</p>","PeriodicalId":18206,"journal":{"name":"mAbs","volume":null,"pages":null},"PeriodicalIF":5.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/4f/9e/KMAB_15_2254676.PMC10498814.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10294479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}