Antibody Therapeutics最新文献

{"title":"Development of a human glioblastoma model using humanized DRAG mice for immunotherapy","authors":"Rashmi Srivastava, Alireza Labani-Motlagh, Apeng Chen, Jose Alejandro Bohorquez, Bin Qin, Meghana Dodda, Fan Yang, Danish Ansari, Sahil Patel, Honglong Ji, Scott Trasti, Yapeng Chao, Yash Patel, Han Zou, Baoli Hu, Guohua Yi","doi":"10.1093/abt/tbad021","DOIUrl":"https://doi.org/10.1093/abt/tbad021","url":null,"abstract":"Abstract Glioblastoma (GBM) is the most common and lethal primary brain tumor. The development of alternative humanized mouse models with fully functional human immune cells will potentially accelerate the progress of GBM immunotherapy. We successfully generated humanized DRAG (NOD.Rag1KO.IL2RγcKO) mouse model by transplantation of human DR4+ hematopoietic stem cells (hHSCs), and effectively grafted GBM patient-derived tumorsphere cells to form xenografted tumors intracranially. The engrafted tumors recapitulated the pathological features and the immune cell composition of human GBM. Administration of anti-human PD-1 antibodies in these tumor-bearing humanized DRAG mice decreased the major tumor-infiltrating immunosuppressive cell populations, including CD4+PD-1+ and CD8+PD-1+ T cells, CD11b+CD14+HLA-DR+ macrophages, CD11b+CD14+HLA-DR−CD15− and CD11b+CD14−CD15+ myeloid-derived suppressor cells, indicating the humanized DRAG mice as a useful model to test the efficacy of GBM immunotherapy. Taken together, these results suggest that the humanized DRAG mouse model is a reliable preclinical platform for studying brain cancer immunotherapy and beyond.","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"49 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135548761","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":"Bringing cell therapy to tumors: considerations for optimal CAR binder design.","authors":"Richard Smith","doi":"10.1093/abt/tbad019","DOIUrl":"10.1093/abt/tbad019","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR)-T cells have revolutionized the immunotherapy of B-cell malignancies and are poised to expand the range of their impact across a broad range of oncology and non-oncology indications. Critical to the success of a given CAR is the choice of binding domain, as this is the key driver for specificity and plays an important role (along with the rest of the CAR structure) in determining efficacy, potency and durability of the cell therapy. While antibodies have proven to be effective sources of CAR binding domains, it has become apparent that the desired attributes for a CAR binding domain do differ from those of a recombinant antibody. This review will address key factors that need to be considered in choosing the optimal binding domain for a given CAR and how binder properties influence and are influenced by the rest of the CAR.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"6 4","pages":"225-239"},"PeriodicalIF":0.0,"publicationDate":"2023-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10576856/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41239487","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}

{"title":"IMM47, a humanized monoclonal antibody that targets CD24, exhibits exceptional anti-tumor efficacy by blocking the CD24/Siglec-10 interaction and can be used as monotherapy or in combination with anti-PD1 antibodies for cancer immunotherapy.","authors":"Song Li, Dianze Chen, Huiqin Guo, Yanan Yang, Dandan Liu, Chunmei Yang, Xing Bai, Wei Zhang, Li Zhang, Gui Zhao, Xiaoping Tu, Liang Peng, Sijin Liu, Yongping Song, Zhongxing Jiang, Ruliang Zhang, Jifeng Yu, Wenzhi Tian","doi":"10.1093/abt/tbad020","DOIUrl":"10.1093/abt/tbad020","url":null,"abstract":"<p><p>This study evaluates the anti-tumor mechanism of IMM47, a humanized anti-CD24 mAb. Biolayer interferometry, ELISA and flow cytometry methods were used to measure the IMM47 binding, affinity, ADCC, ADCP, ADCT and CDC activities. <i>In vivo</i> therapeutical efficacy was measured in transplanted mouse models. IMM47 significantly binds granulocytes but not human erythrocytes and blocks CD24's ability to bind to Siglec-10. IMM47 has strong ADCC, ADCT and ADCP activity against REH cells. IMM47's <i>in vivo</i> pharmacodynamics showed that IMM47 has strong anti-tumor effects in human siglec-10 transgenic mouse models with a memory immune response. IMM47 also has powerful synergistic therapeutic efficacy when combined with Tislelizumab, Opdivo and Keytruda, by blocking CD24/Siglec-10 interaction through macrophage antigen presentation with strong ADCC, ADCP, ADCT and CDC activities and with a safe profile. IMM47 binding to CD24 is independent of N-glycosylation modification of the extracellular domain.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"6 4","pages":"240-252"},"PeriodicalIF":0.0,"publicationDate":"2023-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10576855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41239488","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}

{"title":"Comparability strategy and demonstration for post-approval production cell line change of a bevacizumab biosimilar IBI305.","authors":"Zhouyi Wu, Gangling Xu, Wu He, Chuanfei Yu, Wanqiu Huang, Shirui Zheng, Dian Kang, Michael H Xie, Xingjun Cao, Lan Wang, Kaikun Wei","doi":"10.1093/abt/tbad017","DOIUrl":"10.1093/abt/tbad017","url":null,"abstract":"<p><p>High-producing cell line could improve the affordability and availability of biotherapeutic products. A post-approval production cell line change, low-titer CHO-K1S to high-titer CHO-K1SV GS-KO, was performed for a China marketed bevacizumab biosimilar IBI305. Currently, there is no regulatory guideline specifically addressing the requirements for comparability study of post-approval cell line change, which is generally regarded as the most complex process change for biological products. Following the quality by design principle and risk assessment, an extensive analytical characterization and three-way comparison was performed by using a panel of advanced analytical methods. Orthogonal and state-of-the-art techniques including nuclear magnetic resonance and high-resolution mass spectrometry were applied to mitigate the potential uncertainties of higher-order structures and to exclude any new sequence variants, scrambled disulfide bonds, glycan moiety and undesired process-related impurities such as host cell proteins. Nonclinical and clinical pharmacokinetics (PK) studies were conducted subsequently to further confirm the comparability. The results demonstrated that the post-change IBI305 was analytically comparable to the pre-change one and similar to the reference product in physicochemical and biological properties, as well as the degradation behaviors in accelerated stability and forced degradation studies. The comparability was further confirmed by comparable PK, pharmacodynamics, toxicological and immunogenicity profiles of nonclinical and clinical studies. The comparability strategy presented here might extend to cell line changes of other post-approval biological products, and particularly set a precedent in China for post-approval cell line change of commercialized biosimilars.</p>","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":"6 3","pages":"194-210"},"PeriodicalIF":0.0,"publicationDate":"2023-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/38/cd/tbad017.PMC10481892.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10186515","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}

{"title":"CAMEL NANOBODY-BASED B7-H3 CAR-T CELLS WITH HIGH EFFICACY AGAINST SOLID TUMORS","authors":"Dan Li, Ruixue Wang, Tianyuzhou Liang, Hua Ren, Chaelee Park, Chin-Hsien Tai, Weiming Ni, Jing Zhou, S. Mackay, Elijah Edmondson, Javed Khan, B. S. Croix, Mitchell Ho","doi":"10.1093/abt/tbad014.005","DOIUrl":"https://doi.org/10.1093/abt/tbad014.005","url":null,"abstract":"Abstract Background and significance Chimeric antigen receptor (CAR)-T cell therapy shows promising potency for treating patients with hematological malignancies. However, follow-up data indicate that only 30% to 50% of these patients experience long-term disease control. In solid tumors, the B7-H3 transmembrane protein is an emerging target that harbors in its ectodomain two distinct epitope motifs - IgC and IgV. Here, we developed nanobody-based CAR-T cell strategy targeting B7-H3 and investigated its anti-tumor efficacy in xenograft mouse models. Methods We isolated anti-B7-H3 VHHs from our large dromedary camel VHH nanobody libraries with great diversity (> 1012 total) by phage display technology. The binding of isolated VHHs was validated by ELISA, flow cytometry, and Octet. A B7-H3 peptide library was synthesized to predict the epitope of select VHHs. Anti-tumor effect of B7-H3 CAR-T cells was determined via cell luciferase-based cell killing assay as well as xenograft mouse models. Two tumor models, human neuroblastoma and pancreatic adenocarcinoma, were used in the present study. Single-cell transcriptome RNA sequencing coupled with single T-cell functional proteomics analysis was used to analyze the functionality of nanobody-based B7-H3 CAR-T cells. Results We analyzed the isoforms of B7-H3 at the RNA and protein levels and validated that only 4IgB7-H3 is a therapeutic target as the dominant isoform in tumors. Targeting 4Ig isoform, we obtained a panel of high-affinity nanobodies cross-reactive to human, mouse, rat, and monkey. Furthermore, we demonstrated that CAR-T cells based on the nanobodies had potent antitumor activity against tumors with rigorous T cell signaling and significant tumor infiltration. Mechanistically, we uncovered the top-upregulated genes that might be critical for the persistence of polyfunctional CAR-T cells in the tumor microenvironment. Conclusions Our results provide a novel nanobody-based B7-H3 CAR-T product for use in solid tumor therapy.","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41630739","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":"ESTABLISHMENT OF AN ULTRA HIGH-THROUGHPUT PROTEIN PRODUCTION PLATFORM (ULTRA 96) FOR EARLY STAGE IN VITRO STUDIES","authors":"Kai Jiang, Huishuai Li, Chuanlong Tang, Dawei Zhang, Xuejian Zhang, Ying Zhang, Zhengyang Zhao, Junqing Zhou, Mengjie Lu, Yongsheng Xiao, Zhumei Feng, Jiansheng Wu","doi":"10.1093/abt/tbad014.017","DOIUrl":"https://doi.org/10.1093/abt/tbad014.017","url":null,"abstract":"Abstract Proteins are known as the building blocks of life which play many critical roles in the body. In early stage drug discovery, numerous μg to mg scale high quality proteins need to be produced for in vitro functional studies and therapeutic evaluation, including antigens, monoclonal antibodies (mAb), bispecific antibodies (bsAbs) as well as other Fc fusion proteins. High-throughput production (HTP) of various proteins with high quality in very short time is a big challenge in industry. Here we present how WuXi Biologics has created a powerful ultra HTP protein production platform (termed as “Ultra 96”) that can automatically produce proteins within 3 weeks with one step purification at 1~3mL expression scale by using 96 and 24 well DWP. High titer of expression, high quality of products, short timeline as well as low cost make “Ultra 96” a robust platform which can empower our clients and dramatically accelerate their early stage drug discovery projects.","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43240558","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":"3H-3000, AN FGFR2B-SPECIFIC MONOCLONAL ANTIBODY, SHOWS SUPERIOR TUMOR KILLING IN VIVO","authors":"You Li, Jianwei Zhang, Ruiqin Wang, Xueying Yin, Susan Liu, Jufang Lin, Shaojing Hu, M. Cai","doi":"10.1093/abt/tbad014.016","DOIUrl":"https://doi.org/10.1093/abt/tbad014.016","url":null,"abstract":"Abstract Background and significance Fibroblast growth factor receptor 2b (FGFR2b), a splice isoform of FGFR2, is found to overexpress across multiple cancers types and promotes dysregulated tyrosine kinase activation, resulting in tumor cell proliferation and unchecked malignancy. Cohort studies reveal FGFR2b overexpression and/or amplification in Gastric cancer (~30.2%), squamous non-small cell lung cancer (~20.8%), and endometrial carcinoma (~40%). About 80–85% patients who have advanced HER2-negative gastro-esophageal cancer undergoes approximately 12-14 months of median overall survival (mOS). Thus, there is an urgent need for novel and effective molecular targeted agents. With the recent advancement of mechanistic studies, however, FGFR2b is becoming the optimal target of multiple modalities such as mAb, bispecifics, or antibody-drug conjugate. Bemarituzumab, a FGFR2b blocking antibody, developed by Five Prime clinically demonstrates the safety of FGFR2b target and exhibits preliminary efficacy in advanced GE/GEJ adenocarcinoma patients with overexpression of FGFR2 in at least 5% or 10% of tumor cells. 3H Pharmaceuticals developed a FGFR2b-specific mAb, 3H-3000, of high-affinity, differentiated epitope and enhanced ADCC effect for FGFR2b-overexpressing gastric cancer or other FGFR2b-associated cancer types. In the meantime, we will also explore the versatility of this mAb in other format and in the combination with small molecules that will bring about a wider therapeutic spectrum. Method and Result 3H-3000 is a humanized IgG1kappa antibody with a single digit nM affinity for FGFR2b and no binding to other FGFR2 isoforms. 3H-3000 shows potent proliferation-inhibitive effects on FGFR2b-overexpressing human tumor cells. In gastric cancer cell line SNU16, 3H-3000 can fully inhibit FGF7-induced phosphorylation of FGFR2b and SNU16 proliferation in vitro. On top of signaling blocking, we strongly believe efficacy of antibody-dependent cell cytotoxicity (ADCC) is another viable mechanism for growth factor-targeting therapy. Therefore, 3H-3000 was further engineered with a 20-fold ADCC enhancement which is validated through a CD16-F158 variant-based reporter system. In FGFR2b-overexpressing human gastric cancer SNU16 or OCUM-2M xenograft model, 3H-3000 was shown to inhibit tumor growth and even induce regression, which is rather unexpected given the relative low expression of FGFR2b on SNU16 and none of the competitors exhibit similar phenomenon. With potent efficacy of tumor inhibition and killing, and excellent biophysical characteristics and developability of 3H-3000, we expect to push the molecule to clinical development in the middle of 2024. Conclusion 3H-3000 is a potent FGFR2b blocker with well-defined ADCC efficacy enhancement. It demonstrates strong blocking activity of FGFR2 signaling, strikingly enhanced ADCC activity in vitro and potent efficacy of tumor inhibition in vivo. These data strongly support its clinical development in FGFR2b","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45865901","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":"YEAST SURFACE DISPLAY OF FULL-LENGTH IGG FOR ENGINEERING MONOCLONAL AND BISPECIFIC ANTIBODIES","authors":"Youwei Jiang","doi":"10.1093/abt/tbad014.022","DOIUrl":"https://doi.org/10.1093/abt/tbad014.022","url":null,"abstract":"Abstract The single-chain variable fragment (scFv) and antigen-binding fragment (Fab) are widely used in yeast surface display for antibody engineering. However, these non-IgG antibody fragments are not always well-expressed or functional. We developed a novel approach to display full-length IgG on yeast surfaces for engineering monoclonal and bispecific antibodies. The yeast surface display of full-length IgG was generated by transforming glycoengineered yeast P. pastoris with plasmids encoding for anchor protein, heavy chains, and light chains. IgG-displaying yeast cells were incubated with the fluorophore antigen and secondary detection antibody for FACS sorting. The displayed antibody with bound antigen and detection antibody was detected by FACS sorting based on both antibody affinity and display level. FACS sorting could eliminate the deviation caused by expression levels. The yeast surface display of IgG-like bispecific antibodies was also constructed, which exhibited specific binding of two distinct fluorophore antigens in flow-cytometry analysis. Thus, our yeast surface display of full-length IgG can be used to screen light chain libraries to isolate common light chains for bispecific antibodies. To assess antigen-binding efficiency between different displaying formats, an antibody was respectively displayed as full-length IgG or Fab on the surface of yeast cells for flow-cytometry analysis. Cells displaying full-length IgG showed a higher level of fluorescence than those displaying Fab fragments, indicating that yeast surface display of full-length IgG is superior for high-throughput screening. To test the specificity of the displayed antibody, we performed a demo experiment in which TNF-binding adalimumab-displaying cells were mixed with trastuzumab-displaying cells at a 1 to 1,000,000 ratio, mimicking the immune library. After three consecutive rounds of sorting, the yeast cells with high fluorescence were plated on a selective medium and the individual antibody clones were sequenced. All ten sequenced clones were confirmed to be adalimumab, demonstrating the maintenance of genotype-phenotype linkage for library screening in yeast surface display of full-length IgG. A mutation library was also generated from the initial hit and displayed at the surface of yeast cells for the screening of higher affinity maturation antibodies by FACS. A pool of high-affinity binders was plated on a selective medium. Individual clones were analyzed by flow cytometry and sequenced to identify unique antibodies with higher affinity. In summary, full-length IgG antibodies can be displayed on the yeast cell surface, mimicking their native forms in molecular structure and biophysical properties. The technique combines the high throughput of yeast display with mammalian-cell quality control. This novel approach can be used to engineer monoclonal and bispecific antibodies for high affinity and improved developability profiles.","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43672685","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":"A NOVEL B7H3/NKP30 BISPECIFIC NK CELL ENGAGER FOR CANCER IMMUNOTHERAPY","authors":"Xiaoling Jiang, Chongbing Wu, Zi Chen, Liusong Yin","doi":"10.1093/abt/tbad014.013","DOIUrl":"https://doi.org/10.1093/abt/tbad014.013","url":null,"abstract":"Abstract Background and Significance Biological therapies harnessing the adaptive immune system have achieved a great success, given the clinical efficacy of CAR-T therapies and CD3 based T cell engagers in treating hematologic tumors, and the application of T cell immune checkpoint inhibitors in various indications. However, the challenges still exist due to the limitation of CAR-T therapies and T cell engagers in treating solid tumors. Side effects such as cytokine release storm and neurotoxicity remain a concern in the selection of CAR-T therapies and CD3-based T cell engagers as therapeutics. For PD1/L1-based immunotherapy, the relatively low objective response rate (ORR), short progression-free survival (PFS) of patients, and drug resistance and recurrence especially for solid malignancy, are the major clinical challenges. In contrast, innate effector cells such as NK cells and macrophages are naturally existing in human body as front line to defeat general pathogens and cancers，which will have a better safety profile. Also, NK cell activation is not limited by the antigen presentation of the MHC on the cell surface which makes it has broader anti-tumor effects. However, the innate effector cell based therapy is facing the limitation of low cell number, poor in vitro activation, and short effective duration in vivo. SunHo has generated a B7H3/NKp30 NK cell engager bispecific antibody which can directly activate and enrich NK cells to the TME when used alone or enhance the efficacy when used in combination NK cell therapy. NKp30 is a potent NK cell activation receptor with wide and persistent expression compared with other NK markers. B7H3 as a tumor associate antigen is also widely expressed on many kinds of tumor cells with great potential for multiple indications, especially for solid tumors. Methods Three anti-NKp30 VHHs were identified from Alpaca immunized library. The VHHs were fused to the N-terminus or C-terminus of an anti-B7H3 mAb heavy chain with different IgG isotypes (IgG1 or IgG4). The binding activity to NK cells was evaluated by FACS. IFNγ level was detected in the NK cell activation assay. The NK cell mediated target cell killing was evaluated using either NK92MI-cd16a or Primary NK cells as effector cells. To evaluate the non-specific self-killing of NK cell without target cell, the B7H3/NKp30 candidates were incubated with NK92MI-cd16a and cell lysis percentage were calculated. NSG mice bearing Hs.746T tumors were used to evaluate the in vivo efficacy of B7H3/NKp30 candidates. Results The B7H3/NKp30 candidates showed good binding activity and better activation to NK cells compared with benchmarks. Notably, the B7H3/NKp30 candidate IAN0982-VHH25 with NKp30 fused to the C-terminal with an IgG1 isotype showed lowest risk of non-specific NK cell killing. In the in vivo study, B7H3/NKp30 candidates in combination with 1x106 NK cells showed excellent anti-tumor activity with TGI over 95%. And we didn’t observe any significant ch","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41445974","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":"DEVELOPMENT OF A SELECTIVE CD16A-BASED NK CELL ENGAGER UTILIZING ANTIBODIES TARGETING A SINGLE AMINO ACID VARIATION","authors":"Wuxiang Liao, Christine Tumanut, Lin Li, A. Corper, D. Challa, Alex Chang, Hydari Begum, Elinaz Farokhi, C. Woods, Xiaomin Fan","doi":"10.1093/abt/tbad014.012","DOIUrl":"https://doi.org/10.1093/abt/tbad014.012","url":null,"abstract":"Abstract Background and Significance Natural killer (NK) cells play a vital role in the human innate immune system and are being explored as a promising approach for cancer immunotherapy. Of particular interest are NK cell engagers that can target and activate NK cells to attack cancer cells. In this study, we developed novel NK cell engagers by targeting the NK cell activating receptor CD16a using antibodies that selectively distinguish between CD16a on NK cells and CD16b on granulocytes, which are highly homologous to each other. Methods and Results To generate antibodies with high developability, we employed a rational design approach to construct large yeast display libraries of human antibodies. This approach was based on the analysis of a deep sequencing dataset of human antibodies from over 500 individuals, which allowed us to determine the natural amino acid usage patterns of human antibody CDRs and mimic human antibody repertoires. Through screening these libraries, we discovered two classes of antibody clones that selectively recognize CD16a without cross-reactivity to CD16b. Epitope mapping revealed that a single amino acid difference confers over 10,000-fold selectivity for one class of antibody clones, while for the other class a second unique epitope on CD16a was identified. To evaluate the activity of these antibody clones, we produced bispecific antibody clones with one arm targeting CD16a and the other arm targeting a tumor-associated antigen (TAA). Our results demonstrated potent tumor cell-dependent activation of NK cells and effective killing of tumor cells. Several of these antibodies had greatly enhanced resistance to human IgG inhibition in killing target cells. Significantly, our anti-CD16a antibody clones exhibited superior performance compared to leading reference anti-CD16a clones in two distinct NK cell engager formats. This included higher affinity for CD16a, higher thermostability, and more potent killing activity both in the absence and presence of 10 mg/mL human IgGs as competitors. Conclusion Our findings indicate that anti-CD16a antibody-based NK cell engagers have significant potential for cancer immunotherapies.","PeriodicalId":36655,"journal":{"name":"Antibody Therapeutics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46124421","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}