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Rapid qualitative antigen testing is essential in the clinical management of COVID-19. However, most evaluations of antigen tests have been performed before the emergence of the Omicron variant.This prospective observational study evaluated QuickNavi-COVID19 Ag, a rapid antigen detection test between December 2021 and February 2022 in Japan, using real-time reverse transcription (RT)-PCR as a reference. Two nasopharyngeal samples were simultaneously collected for antigen testing and for RT-PCR. Variant analysis of the SARS-CoV-2 genomic sequencing was also performed.In total, nasopharyngeal samples were collected from 1073 participants (417 positive; 919 symptomatic; 154 asymptomatic) for analysis. Compared with those of RT-PCR, the sensitivity, specificity, positive predictive value, and negative predictive value were 94.2% (95% CI: 91.6%-96.3%), 99.5% (95% CI: 98.7%-99.9%), 99.2% (95% CI: 97.8%-99.8%), and 96.5% (95% CI: 94.8%-97.7%), respectively. The sensitivity among symptomatic individuals was 94.3% (95% CI: 91.5%-96.4%). Overall, 85.9% of sequences were classified as Omicron sublineage BA.1, 12.4% were Omicron sublineage BA.2, and 1.6% were Delta B.1.617.2. (Delta variant). Most of the samples (87.1%) had Ct values of25, and the sensitivity was 47.4% for low viral load samples (Ct ≥ 30); a similar trend has been observed in both symptomatic and asymptomatic groups.The QuickNavi-COVID19 Ag test showed sufficient diagnostic performance for the detection of the SARS-CoV-2 Omicron sublineages BA.1 and BA.2 from nasopharyngeal samples. However, the current study was mainly performed in symptomatic patients and the results are not sufficiently applicable for asymptomatic patients.

Previously, we reported the fundamental pharmacological characteristics of a novel Igβ and Fc gamma receptor IIB cross-linking antibody, ASP2713, as a new treatment option for systemic lupus erythematosus. The aims of the present study were to investigate ASP2713's characteristics with regard to pharmacological effect, pharmacokinetics (PK), and receptor occupancy, and to predict its human PK and clinically effective dose. The relationship between the concentration and receptor occupancy of ASP2713 for Igβ of B cell receptors was examined using whole blood B cells. Calculated EC

Dose finding in vivo study of IMD-0354.

Epithelial ovarian cancer (EOC) cells metastasize within the peritoneal cavity and directly encounter human peritoneal mesothelial cells (HPMC) as the initial step of metastasis. The contact between ovarian cancer cells and the single layer of mesothelial cells involves direct communications that modulate cancer progression but the mechanisms are unclear. One candidate mediating cell–cell communications is exosomes, 30–100 nm membrane vesicles of endocytic origin, through the cell–cell transfer of proteins, mRNAs, or microRNAs. Therefore, the goal was to mechanistically characterize how EOC-derived exosomes modulate metastasis. Exosomes from ovarian cancer cells were fluorescently labeled and cocultured with HPMCs which internalized the exosomes. Upon exosome uptake, HPMCs underwent a change in cellular morphology to a mesenchymal, spindle phenotype. CD44, a cell surface glycoprotein, was found to be enriched in the cancer cell–derived exosomes, transferred, and internalized to HPMCs, leading to high levels of CD44 in HPMCs. This increased CD44 expression in HPMCs promoted cancer invasion by inducing the HPMCs to secrete MMP9 and by cleaning the mesothelial barrier for improved cancer cell invasion. When CD44 expression was knocked down in cancer cells, exosomes had fewer effects on HPMCs. The inhibition of exosome release from cancer cells blocked CD44 internalization in HPMCs and suppressed ovarian cancer invasion. In ovarian cancer omental metastasis, positive CD44 expression was observed in those mesothelial cells that directly interacted with cancer cells, whereas CD44 expression was negative in the mesothelial cells remote from the invading edge. This study indicates that ovarian cancer–derived exosomes transfer CD44 to HPMCs, facilitating cancer invasion.Implications: Mechanistic insight from the current study suggests that therapeutic targeting of exosomes may be beneficial in treating ovarian cancer. Mol Cancer Res; 15(1); 78–92. ©2016 AACR.

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The prolongation of progression-free survival (PFS) in patients with advanced ovarian cancer by antiangiogenic therapy has been shown in several clinical trials. However, although an anti-VEGF antibody (bevacizumab) is the only option currently available, its efficacy is limited and it is not cost effective for use in all patients. Therefore, the development of a novel antiangiogenic drug, especially composed of small-molecule compounds, could be a powerful armament for ovarian cancer treatment. As NF-κB signaling has the potential to regulate VEGF expression, we determined to identify whether VEGF expression is associated with NF-κB activation and to investigate the possibility of a novel IKKβ inhibitor, IMD-0354 (IMMD Inc.), as an antiangiogenic drug. Tissue microarrays from 94 ovarian cancer tissues were constructed and immunohistochemical analyses performed. We revealed that IKK phosphorylation is an independent prognostic factor (PFS: 26.1 vs. 49.8 months, P = 0.011), and is positively correlated with high VEGF expression. In in vitro analyses, IMD-0354 robustly inhibited adhesive and invasive activities of ovarian cancer cells without impairing cell viabilities. IMD-0354 significantly suppressed VEGF production from cancer cells, which led to the inhibition of angiogenesis. In a xenograft model, the treatment of IMD-0354 significantly inhibited peritoneal dissemination with a marked reduction of intratumoral blood vessel formation followed by the inhibition of VEGF expression from cancer cells. IMD-0354 is a stable small-molecule drug and has already been administered safely to humans in other trials. Antiangiogenic therapy targeting IKKβ is a potential future option to treat ovarian cancer. Mol Cancer Ther; 14(4); 909–19. ©2015 AACR.

Characteristics of 94 ovarian cancer patients.

Multivariate analysis for progression free survival of patients.

Supplementary Figure 1. MMP-9 activity is involved in EOC invasion through HPMC. Supplementary Figure 2. Inhibition of exosome secretion attenuates CD44 uptake by HPMCs and suppresses TYK-nu cell invasion. Supplementary Figure 3. Inhibition of exosome uptake attenuates CD44 expression in HPMCs. Supplementary Figure 4. Immunofluorescent analyses. Supplementary Figure 5. Not only CD44 but MMP-9 are strongly expressed in peritoneal mesothelial cells interacting with ovarian cancer cells. Supplementary Figure 6. Acquisition of CD44 of mouse omental tissues from ovarian cancer cells is dose-dependent. Supplementary Table 1. Clinical characteristics of ovarian cancer patients with stage III-IV consecutively treated at Osaka University Hospital between 2011 and 2015.

Since respiratory sample collection is an uncomfortable experience, simultaneous detection of pathogens with a single swab is preferable. We prospectively evaluated the clinical performance of a newly developed antigen test QuickNavi-Flu+COVID19 Ag (Denka Co., Ltd., Tokyo, Japan) which can detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza viruses at the same time with a single testing device.We included those who were suspected of contracting coronavirus disease 2019 (COVID-19) and were referred to a PCR center at Ibaraki prefecture in Japan, between August 2, 2021 to September 13, 2021, when the variant carrying L452R spike mutation of SARS-CoV-2 were prevalent. Additional nasopharyngeal samples and anterior nasal samples were obtained for the antigen test and were compared with a reference real-time reverse transcription PCR (RT-PCR) using nasopharyngeal samples.In total, 1510 nasopharyngeal samples and 862 anterior nasal samples were evaluated. During the study period, influenza viruses were not detected by QuickNavi-Flu+COVID19 Ag and reference real-time RT-PCR. For SARS-CoV-2 detection in nasopharyngeal samples, the sensitivity and specificity of the antigen test were 80.9% and 99.8%, respectively. The sensitivity and specificity using anterior nasal samples were 67.8% and 100%, respectively. In symptomatic cases, the sensitivities increased to 88.3% with nasopharyngeal samples and 73.7% with anterior nasal samples. There were three cases of discrepant results between the antigen test and the real-time RT-PCR. All of them were positive with the antigen test but negative with the real-time RT-PCR in SARS-CoV-2 detection.A combo kit, QuickNavi-Flu+COVID19 Ag, showed an acceptable sensitivity and sufficient specificity for SARS-CoV-2 detection, especially using nasopharyngeal sample collected from symptomatic patients.

Introduction Smart Gene is a point-of-care (POC)-type automated molecular testing platform that can be performed with 1 min minute of hands-on-time. Smart Gene SARS-CoV-2 is a newly developed Smart Gene molecular assay for the detection of SARS-CoV-2. The analytical and clinical performance of Smart Gene SARS-CoV-2 has not been evaluated. Methods Nasopharyngeal and anterior nasal samples were prospectively collected from subjects referred to the local PCR center from March 25 to July 5, 2021. Two swabs were simultaneously obtained for the Smart Gene SARS-CoV-2 assay and the reference real-time RT-PCR assay, and the results of Smart Gene SARS-CoV-2 were compared to the reference real-time RT-PCR assay. Results Among a total of 1150 samples, 68 of 791 nasopharyngeal samples and 51 of 359 anterior nasal samples were positive for SARS-CoV-2 in the reference real-time RT-PCR assay. In the testing of nasopharyngeal samples, Smart Gene SARS-CoV-2 showed the total, positive and negative concordance of 99.2% (95% confidence interval [CI]: 98.4–99.7%), 94.1% (95% CI: 85.6–98.4%) and 99.7% (95% CI: 99.0–100%), respectively. For anterior nasal samples, Smart Gene SARS-CoV-2 showed the total, positive and negative concordance of 98.9% (95% CI: 97.2–99.7%), 98.0% (95% CI: 89.6–100%) and 99.0% (95% CI: 97.2–99.8%), respectively. In total, 5 samples were positive in the reference real-time RT-PCR assay and negative in the Smart Gene SARS-CoV-2 assay, whereas 5 samples were negative in the reference real-time RT-PCR assay and positive in the Smart Gene SARS-CoV-2 assay. Conclusion Smart Gene SARS-CoV-2 showed sufficient analytical performance for the detection of SARS-CoV-2 in nasopharyngeal and anterior nasal samples.

Antigen tests for severe acute respiratory coronavirus 2 sometimes show positive lines earlier than their specified read time, although the implication of getting the results at earlier time is not well understood. This study aimed to evaluate the clinical utility of an antigen test by evaluating the time period to get positive results and by comparing the test sensitivity with that of a digital immunoassay (DIA) test.We prospectively collected additional nasopharyngeal samples from patients who had already tested positive for SARS-CoV-2 by reverse transcription PCR. The additional swab was used for an antigen test, QuickNavi™-COVID19 Ag, and the time periods to get positive results were measured. The sensitivity of QuickNavi™-COVID19 Ag was also compared with that of a DIA.In 84 of 96 (87.5%) analyzed cases, the results of QuickNavi™-COVID19 Ag were positive. The time to obtain positive results was 15.0 seconds in median (inter quartile range: 12.0-33.3, range 11-736), and was extended in samples with higher cycle thresholds (Ct) (p32.QuickNavi™-COVID19 Ag immediately showed positive results in most cases, and the time to a positive reaction may have indicated the viral load. In addition, the sensitivity of the test was comparable to the DIA.

This study aimed to clarify the changes in the activity of the trunk and lower limb muscles during 2000-m rowing. Ten male rowers performed a 2000-m race simulation on a rowing ergometer. Electromyography results of the abdominal muscles, back muscles, gluteus maximus (GMax), biceps femoris (BF), and rectus femoris (RF) were recorded. The electromyographic activity during the three strokes after the start (initial stage), at 1000m (middle stage), and before the end (final stage) were analyzed. From the handle position, the rowing motion was divided into five phases (early-drive, middle-drive, late-drive, early-recovery, and late-recovery). The peak activities of the abdominal muscles, back muscles, GMax, and BF in each stroke of the rowing motion were delayed at the middle and final stages compared to the initial stage (P0.05). The peak activity of the RF was observed in the late-drive phase at the initial stage, whereas a high RF activity was observed in the middle-drive phase at the middle and final stages (P0.05). Considering the results of the activity of the back muscles and RF, RF muscular endurance enhancement may lead to a decrease in the load on the back muscles and help prevent muscular low back pain in rowers. J. Med. Invest. 69 : 45-50, February, 2022.

The high-grade serous ovarian cancer (HGSOC) risk locus at chromosome 1p34.3 resides within a frequently amplified genomic region signifying the presence of an oncogene. Here, we integrate in silico variant-to-function analysis with functional studies to characterize the oncogenic potential of candidate genes in the 1p34.3 locus. Fine mapping of genome-wide association statistics identified candidate causal SNPs local to H3K27ac-demarcated enhancer regions that exhibit allele-specific binding for CTCF in HGSOC and normal fallopian tube secretory epithelium cells (FTSECs). SNP risk associations colocalized with eQTL for six genes (DNALI1, GNL2, RSPO1, SNIP1, MEAF6, and LINC01137) that are more highly expressed in carriers of the risk allele, and three (DNALI1, GNL2, and RSPO1) were upregulated in HGSOC compared to normal ovarian surface epithelium cells and/or FTSECs. Increased expression of GNL2 and MEAF6 was associated with shorter survival in HGSOC with 1p34.3 amplifications. Despite its activation of β-catenin signaling, RSPO1 overexpression exerted no effects on proliferation or colony formation in our study of ovarian cancer and FTSECs. Instead, GNL2, MEAF6, and SNIP1 silencing impaired in vitro ovarian cancer cell growth. Additionally, GNL2 silencing diminished xenograft tumor formation, whereas overexpression stimulated proliferation and colony formation in FTSECs. GNL2 influences 60S ribosomal subunit maturation and global protein synthesis in ovarian cancer and FTSECs, providing a potential mechanism of how GNL2 upregulation might promote ovarian cancer development and mediate genetic susceptibility of HGSOC.

This Figure shows the appearance of melanomas as well as the survival and tumor number of the different chimera models.

This Figure shows the efficiency of Pten silencing using Cre/loxP, shRNA and CRISPR as well as chimera contribution of targeted ES cells.

The cumbersome and time-consuming process of generating new mouse strains and multiallelic experimental animals often hinders the use of genetically engineered mouse models (GEMM) in cancer research. Here, we describe the development and validation of an embryonic stem cell (ESC)-GEMM platform for rapid modeling of melanoma in mice. The platform incorporates 12 clinically relevant genotypes composed of combinations of four driver alleles (LSL-BrafV600E, LSL-NrasQ61R, PtenFlox, and Cdkn2aFlox) and regulatory alleles to spatiotemporally control the perturbation of genes of interest. The ESCs produce high-contribution chimeras, which recapitulate the melanoma phenotypes of conventionally bred mice. Using the ESC-GEMM platform to modulate Pten expression in melanocytes in vivo, we highlighted the utility and advantages of gene depletion by CRISPR-Cas9, RNAi, or conditional knockout for melanoma modeling. Moreover, complementary genetic methods demonstrated the impact of Pten restoration on the prevention and maintenance of Pten-deficient melanomas. Finally, we showed that chimera-derived melanoma cell lines retain regulatory allele competency and are a powerful resource to complement ESC-GEMM chimera experiments in vitro and in syngeneic grafts in vivo. Thus, when combined with sophisticated genetic tools, the ESC-GEMM platform enables rapid, high-throughput, and versatile studies aimed at addressing outstanding questions in melanoma biology.Significance: This study presents a high-throughput and versatile ES cell-based mouse modeling platform that can be combined with state-of-the-art genetic tools to address unanswered questions in melanoma in vivo.See related commentary by Thorkelsson et al., p. 655

This file contains a detailed description of the Materials and Methods used, as well as the Supplementary Figure Legends

IntroductionRapid qualitative antigen testing has been widely used for the laboratory diagnosis of COVID-19 with nasopharyngeal samples. Saliva samples have been used as alternative samples, but the analytical performance of those samples for qualitative antigen testing has not been sufficiently evaluated.MethodsA prospective observational study evaluated the analytical performance of three In Vitro Diagnostics (IVD) approved COVID-19 rapid antigen detection kits for saliva between June 2022 and July 2022 in Japan using real-time reverse transcription polymerase chain reaction (RT-PCR) as a reference. A nasopharyngeal sample and a saliva sample were simultaneously obtained, and RT-PCR was performed.ResultsIn total, saliva samples and nasopharyngeal samples were collected from 471 participants (140 RT-PCR-positive saliva samples and 143 RT-PCR-positive nasopharyngeal samples) for the analysis. The median Ct values were 25.5 (interquartile range [IQR]: 21.9-28.8) for saliva samples and 17.1 (IQR: 15.5-18.7) for nasopharyngeal samples (p90% for saliva samples with a moderate-to-high viral load (CtConclusionCOVID-19 rapid antigen detection kits with saliva showed high specificities, but the sensitivities varied among kits, and the analytical performance of saliva qualitative antigen detection kits was much worse than that of kits using nasopharyngeal samples.

Systemic lupus erythematosus (SLE) is an autoimmune disease involving multi-organ systems with a widely heterogeneous clinical presentation. Renal involvement, observed mainly in lupus nephritis (LN), is the most common organ lesion associated with SLE and a determinant of prognosis. However, treatment of LN remains controversial and challenging, prompting the need for novel therapeutic approaches. In particular, development of a clinically relevant LN animal model would greatly facilitate the development of new treatments. Here, we report a novel murine model for LN established by administering polyinosinic-polycytidylic acid (Poly (I:C)) to NZB/W F1 mice. We investigated the effectiveness of administering Poly (I:C) to NZB/W F1 mice for accelerating nephritis onset and explored the optimal conditions under which to enroll mice with nephritis with similar pathology for studying treatment candidates. Gene-expression analysis revealed that activation of macrophages, which are reported to be involved in the progression of LN in patients, was a unique characteristic in this accelerated nephritis model. Evaluation of the therapeutic effect of mycophenolate mofetil (MMF), a recommended first-choice agent for LN, in this novel LN model showed that MMF significantly reduced proteinuria. The cathepsin S (CatS) inhibitor ASP1617, which has been reported to prevent development of lupus-like glomerulonephritis in the spontaneous NZB/W F1 mouse model, also showed marked therapeutic effect in this model. Our novel Poly (I:C) accelerated LN model would thus be very useful for screening clinical candidates for LN, and CatS may be an attractive therapeutic target for the treatment of LN.

Molecular tests are the mainstay of detecting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, their accessibility can be limited by the long examination time and inability to evaluate multiple samples at once. This study evaluated the analytical performance of the newly developed rapid molecular assays GENECUBE® HQ SARS-CoV-2 and GENECUBE® FLU A/B. This prospective study was conducted between 14 December 2020 and 9 January 2021 at a polymerase chain reaction (PCR) center. Samples were collected from the nasopharynx with flocked swabs. Molecular tests were performed with the GENECUBE® system and reference reverse transcription (RT)-PCR, and the results of the two assays were compared. Among 1065 samples, 81 (7.6%) were positive for SARS-CoV-2 on the reference RT-PCR. Three showed discordance between GENECUBE® HQ SARS-CoV-2 and the reference RT-PCR; the total, positive, and negative samples of concordance for the two assays were 99.7%, 100%, and 99.7%, respectively. All discordant cases were positive with GENECUBE® HQ SARS-CoV-2 and negative with the reference RT-PCR. SARS-CoV-2 was detected in all three samples using another molecular assay for SARS-CoV-2. For GENECUBE® FLU A/B, the total, positive, and negative samples of concordance for the two assays were 99.5%, 100%, and 99.1%. The GENECUBE® HQ SARS-CoV-2 and GENECUBE® FLU A/B demonstrated sufficient analytical performance to detect SARS-CoV-2 and influenza virus A/B.

5T4 oncofetal tumor-associated antigen (also known as TPGB or WAIF1) is over-expressed in a wide range of solid tumors but shows very limited expression in normal adult tissues thus suggesting 5T4 as an attractive target for antibody therapy. CBA-1535, originally developed by Biotecnol (UK), is a novel trivalent biological construct named a Tribody™ with two binding sites to the tumor associated antigen 5T4 and one to the T cell expressed antigen CD3ε. CD-3 based T cell engagers (TCE) is one of the attractive strategy to treat cancer patients resistant to conventional therapies, however, the effects of TCE on solid tumors are limited due to the immunosuppressive tumor microenvironment. To overcome this limitation, CBA-1535 is designed to have stronger binding activity to 5T4 with two binding sites, and to have the lower affinity to CD3 than to 5T4 to prevent non-specific T cell activation.CBA-1535 does not have a Fc region with a molecular weight of ~100 kDa and it has a low nM Kd for bivalent binding to 5T4, a 20 to 30 nM Kd for monovalent binding to CD3ε. CBA-1535 efficiently induced T cell activation in human PBMCs as exemplified as CD25 and CD69 expressions and showed cytokine release, i.e., IL-2, IL-6, TNFα, and IFN-ɤ, at the concentration between 0.01 and 10 nM only when co-cultured with target cancer cells, however, those T cell activation and cytokine release were not observed under the conditions without target cancer cells, even at the concentration of 1 µM. In the presence of activated human PBMCs as effector cells, CB-1535 elicited 5T4 expressing target cell cytotoxicity with an EC50 of approximately 1-30 pM in a variety of cancer cells. The anti-tumor efficacy of CB-1535 has examined in immunocompromised mice bearing human lung mesothelioma (MSTO-211H) and alveolar epithelial adenocarcinoma (A549) xenografts (such as the 5T4 expressing target cell) and human PBMCs (as effector cells). Anti-tumor efficacy was observed with complete suppression of tumor growth at doses as low as 1 mg/kg in both xenograft models. No abnormalities related to CBA-1535 administration were observed regarding to body weight and clinical signs. Importantly, CBA-1535 showed a synergistic cytotoxicity against 5T4 expressing target cancer cells in vitro when combined with PD-1 antibody Pembrolizumab in a co-culture experiment. In conclusion, we demonstrated encouraging preclinical profile of CBA-1535 as a novel CD-3 based T-cell engager antibody. These results provide the strong rationale for further clinical evaluation of CBA-1535 in 5T4 positive tumors. CBA-1535 is now under the phase 1 trial in Japan (jRCT2031210708), with 2 parts, the monotherapy and the combination with Pembrolizumab. Citation Format: Fumitake Takizawa, Kotaro Yamamoto, Koji Nakamura, Ana R. Richard, Philip J. Cunnah, Nico Mertens, Pedro D. Pissarra, Yukihito Tsukumo. Preclinical characterization of CBA-1535, a novel bi-specific tribody, with two binding sites to 5T4 and one site to CD3ε [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2937.

CUB domain containing protein 1 (CDCP1) is a single transmembrane protein that is highly expressed in a broad range of solid cancers, including lung, breast, colorectal, pancreas, prostate, and ovarian cancers. Although no soluble ligand for CDCP1 is known, CDCP1 transduces signals resulting in cancer cell motility, epithelial mesenchymal transition, and metastasis by activating downstream signaling via homodimerization or heterodimerization with other cell surface molecules such as EGFR, HER2, and ITGB1. Owing to its important roles in cancer, CDCP1 has been reported as a promising therapeutic target for the treatment of solid cancers. While it is overexpressed in many of the abovementioned solid cancer types, several normal tissues such as esophagus, skin, and bone marrow hematopoietic stem cells (HSCs) also express CDCP1. To minimize the risk of toxicity, we generated novel anti-CDCP1 antibodies that bind weakly to bone marrow HSCs. Three isolated anti-CDCP1 monoclonal antibodies and their humanized versions showed weak binding to HSCs compared to other anti-CDCP1 antibodies reported from other groups. Although they only showed moderate binding activity to cancer cell lines, rapid internalization and efficient lysosomal trafficking was observed following CDCP1 binding. Subsequently, we generated antibody drug conjugates (ADCs) of the 3 anti-CDCP1 antibodies using PBD, MMAE, and MMAF as a cytotoxic payload with both a cleavable and non-cleavable linker. All constructed ADCs showed strong anti-tumor activity in multiple cancer cell lines in vitro. The cytotoxic activities of these ADCs were correlated to CDCP1 surface expression levels and internalization activity. The anti-CDCP1 ADCs showed strong anti-tumor efficacy in multiple cell line xenograft models. We selected the clone h14A043 for further evaluation owing to its observed potent anti-tumor activity both in vitro and in vivo. We then constructed h14A043-ATAC (Antibody Targeted Amanitin Conjugate), which has a site-specifically conjugated amanitin derivative with DAR 2 and an Fc domain mutation that reduces the effector function of human IgG1. h14A043-ATAC showed good anti-tumor potency both in vitro and in vivo. In human prostate cancer PC3 cell line xenograft model, we observed significant tumor growth delay following treatment by h14A043-ATAC with a single administration of 0.1 mg/kg. Furthermore, we observed complete tumor remission in 3 out of 8 mice at 40 days after a single administration of 1 mg/kg. In the non-GLP single dose toxicity study using cynomolgus monkeys, h14A043-ATAC showed good serum stability and no hematological toxicity. Our results suggest that ADC using an anti-CDCP1 mAb with weak binding to bone marrow HSC and sufficient internalization activity could provide a new treatment option for refractory solid cancer patients. Citation Format: Shu-ichi Hashimoto, Shiori Miyamoyo, Aki Takaiwa, Koji Nakamura, Yukihito Tsukumo, Yoshinori Yamashita. Antibody drug conjugate using a novel anti-CDCP1 antibody with low hematopoietic stem-cell binding and rapid internalization showed high efficacy for solid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 438.

Objectives Delta-like 1 homolog (DLK1) is a non-canonical Notch ligand known to be expressed in several cancers but whose role in lung cancer is not yet fully understood. We sought to confirm DLK1 expression in small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), and to examine DLK1’s clinical significance. Furthermore, we examined the possible utility of DLK1 as a novel target in radioimmunotherapy (RIT). Methods We retrospectively assessed the correlation between clinical features and DLK1 expression by immunohistochemistry in resected specimens from 112 patients with SCLC and 101 patients with NSCLC. Moreover, we performed cell and animal experiments, and examined the possibility of RIT targeting DLK1 in SCLC using iodine-125 (125I) -labeled anti-DLK1 antibody, knowing that 125I can be replaced with the alpha-particle-emitter astatine-211 (211At). Results In SCLC and NSCLC, 20.5 % (23/112) and 16.8 % (17/101) of patients (respectively) had DLK1-positive tumors. In NSCLC, DLK1 expression was associated with recurrence-free survival (P Conclusion A proportion of SCLC and NSCLC exhibits DLK1 expression. As a clinical feature, DLK1 expression could be a promising prognostic factor for recurrence in patients with resected NSCLC. In addition, DLK1 could serve as a new therapeutic target, including RIT, as suggested by our pilot study using a radiolabeled anti-DLK1 antibody in SCLC.