Duality (United States)

Abstract Background: HER3-targeted antibody-drug conjugates (ADCs) have shown benefits in breast cancer (BC). DB-1310 is a novel ADC comprised of a humanized anti-HER3 IgG1 monoclonal antibody with a highly internalizing unique Domain I epitope, a cleavable peptide linker, and a potent DNA topoisomerase I inhibitor P1021. Initial clinical data demonstrated a manageable safety profile and encouraging anti-tumor activity, particularly in patients with EGFR-mutant NSCLC (Lisberg ASCO 2025). Here, we present the efficacy and safety results of DB-1310 in pretreated hormone receptor-positive (HR+), HER2-negative (HER2-) BC patients. Methods: In the Phase 1 part of this trial (NCT05785741), patients with advanced solid tumors, including HR+/HER2- BC, received DB-1310 monotherapy intravenously every three weeks (Q3W). Safety was the primary endpoint, with efficacy endpoints including objective response rate (ORR), duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) as secondary endpoints. Results: As of July 04, 2025, a total of 207 patients with solid tumors were enrolled and treated with DB-1310 monotherapy (1.5-6.5 mg/kg, Q3W) in Phase 1 (ECOG PS 1, 84.1%; White, 26.1%; Asian, 69.1%). Among these, 16 HR+/HER2- BC patients were enrolled (3.0-5.5 mg/kg, Q3W), with 15 of them being efficacy-evaluable, and a median prior line of systemic therapy was 2 (range, 1-7). Efficacy Results (N=15 HR+/HER2- BC patients from Phase 1): nine achieved a partial response (one pending confirmation), and four achieved stable disease, resulting in a confirmed ORR of 53.3% (95%CI: 26.59, 78.73) and a DCR of 86.7% (95%CI: 59.54, 98.34). Notably, all partial responses occurred in patients treated with 5-5.5 mg/kg (N=13), yielding an unconfirmed ORR of 69.2%, a confirmed ORR of 61.5%, and a DCR of 92.3% for this dose range. The median DoR is not reached. Median PFS is 14.78 months (95% CI: 11.60, not evaluable) and median OS is 14.69 months (95% CI: 11.89, not evaluable). Safety Results (N=207, all enrolled patients from Phase 1): The safety profile was assessed in the entire Phase 1 part. Treatment-related adverse events (TRAEs) of Grade (G) ≥ 3 occurred in 89 (43.0%) patients, and 25 patients (12.1%) had treatment-related serious adverse events. TRAEs led to dose reduction in 38 (18.4%) and discontinuation in 9 (4.3%) patients. No TRAE-related deaths were reported. Most common TRAEs (any grade/≥G3; >20% overall) were neutrophile count decreased (49.3%/ 26.1%), anemia (47.8%/ 6.8%), platelet count decreased (45.4%/ 15.9%), white blood cell count decreased (43.5%/ 11.1%), nausea (40.6%/ 1.0%), decreased appetite (29.5%/ 0.5%), aspartate aminotransferase increased (26.6%/ 0), alopecia (26.1%/ 0), vomiting (24.6%/ 0), and hypoalbuminemia (21.7%/ 0). Interstitial lung disease/pneumonitis occurred in 10 pts (4.8%; one Grade 2, all others G1). The safety profile in the 16 HR+/HER- BC patients was consistent with the overall Phase 1 part. Conclusion: DB-1310 showed promising anti-tumor activity in heavily pretreated HR+/HER2- BC patients. The manageable safety profile observed in the larger Phase 1 part, involving 207 patients, is consistent with that of the BC subpopulation, supporting its further development. Citation Format: Y. Yin, A. Spira, H. Lan, M. Zhao, Y. Mao, W. Yao, Y. Sun, J. Wu, X. Sun, S. Liu, H. Mu, K. Wang, Y. Qiu, E. Hamilton. First clinical data of DB-1310 (HER3-targeted antibody-drug-conjugate), in patients with pretreated hormone receptor-positive/HER2-negative breast cancer: efficacy and safety data from a phase 1/2a trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-06-17.

3000 Background: DB-1310 is a novel ADC comprised of a humanized anti-HER3 IgG1 monoclonal antibody, cleavable peptide linker, and DNA topoisomerase I inhibitor. Here, we report the preliminary results of the FIH trial. Methods: This global, multi-center, open-label Ph 1/2a trial includes dose escalation and expansion. Pts with advanced solid tumors who had failed standard therapy were enrolled. In Ph1, DB-1310 was planned to be administered at doses from 1.5 mg/kg to 6.5 mg/kg, Q3W, iv, using a 3+3 design, with additional pts enrolled to determine the RP2D. Ph 2a will include approximately 30-40 pts per cohort to optimize the RP2D and assess efficacy. Results: As of Jan 17, 2025, 123 pts were enrolled and treated with DB-1310 monotherapy in Ph1 (ECOG PS 1, 80.5%; White, 39.0%, Asian, 52.8%; NSCLC, 65.0%, EGFRm NSCLC, 37.4%; brain metastasis, 17.1%), median prior lines of systemic therapy was 3 (range, 1-11). Of the 42 efficacy-evaluable pts with EGFRm NSCLC, 92.9% had previously received 3 rd generation EGFR TKI, 92.9% had received platinum-based chemotherapy. The unconfirmed ORR was 25.5% (95% CI, 17.63, 34.65) across all tumor types and 35.7% (95% CI, 21.55, 51.97) in EGFRm NSCLC. Median PFS was 5.4 months overall and 7.0 months for EGFRm NSCLC. 38 (30.9%) pts experienced ≥ G3 TRAEs, while 7 (5.7%) had drug-related SAEs. TRAEs led to dose reduction in 14 (11.4%) pts and discontinuation in 5 (4.1%) pts. No TRAE leading to death was reported. Most common TRAE ( > 20%, any grade/≥G3) were nausea (36.6%/0.8%), anemia (35.8%/4.1%), neutrophil count decreased (34.1%/17.9%), platelet count decreased (31.7%/9.8%), white blood cell count decreased (29.3%/8.9%), decreased appetite (23.6%/0.8%), and vomiting (21.1%/0%). Interstitial lung disease occurred in 7 pts (5.7%, 6 G1 and 1 G2). PK exposure was increased through dose escalation, with low systemic payload exposure and no accumulation of DB-1310 upon repeated administration. Conclusions: DB-1310 showed a manageable safety profile and encouraging antitumor activity in pts with heavily pretreated advanced solid tumors, particularly EGFRm NSCLC. Clinical trial information: NCT05785741 . Tumor response by dose (efficacy-evaluable). Dose (mg/kg) 1.5 3 4.5 5.0 5.5 6 Total All tumors, n 3 10 25 53 16 3 110 uORR, n (%) (95% CI) 0 (0)(0.00, 70.76) 1(10.0)(0.25, 44.50) 8 (32.0)(14.95, 53.50) 13 (24.5) (13.76, 38.28) 6 (37.5) (15.20, 64.57) 0 (0)(0.00, 70.76) 28 (25.5) (17.63, 34.65) DCR, n (%) (95% CI) 3 (100.0)(29.24, 100.00) 8 (80.0)(44.39, 97.48) 23 (92.0)(73.97, 99.02) 42 (79.2) (65.89, 89.16) 11 (68.8) (41.34, 88.98) 2 (66.7) (9.43, 99.16) 89 (80.9) (72.31, 87.78%) EGFRm NSCLC, n 0 7 9 16 8 2 42 uORR, n (%) (95% CI) - 1 (14.3)(0.36, 57.87) 4 (44.4) (13.70, 78.80) 5 (31.3) (11.02, 58.66) 5 (62.5) (24.49, 91.48) 0 (0)(0.00, 84.19) 15 (35.7) (21.55, 51.97) DCR, n (%) (95% CI) - 6 (85.7) (42.13, 99.64) 9 (100.0) (66.37, 100.00) 14 (87.5) (61.65, 98.45) 7 (87.5) (47.35, 99.68) 2 (100.0)(15.81, 100.00) 38 (90.5) (77.38, 97.34)

Abstract Background: Both B7H3 and PD-(L)1 are highly expressed in various solid tumors, including lung cancer, hepatocellular cancer, breast cancer, melanoma, and many others. Dual blockade of B7H3 and PD-(L)1 improved antitumor activity compared to either agent alone. However, no bispecific antibodies targeting both PD-(L)1 and B7H3 are in clinical development. DB-1419 is a bispecific antibody-drug conjugate (ADC) comprised of a humanized anti-B7H3/PD-L1 IgG1 antibody covalently linked to a proprietary DNA topoisomerase I inhibitor (P1003) via a cleavable linker containing maleimide tetrapeptide, with a drug-to-antibody ratio of approximately 8. Preclinical studies demonstrated that DB-1419 exhibited both direct cancer cell killing and immune-modulating functions. These studies warrant further clinical development of DB-1419. Methods: This is a multicenter, open-label, multiple-dose, first-in-human Phase 1/2a study (NCT06554795) to assess the safety, tolerability, and anti-tumor activities of the study drug DB-1419 in participants with pretreated advanced/metastatic solid tumors unselected for B7H3/PD-L1 expression. The trial is planned to enroll 360 participants from the United States, Australia, and China (90 in Phase 1a and 270 in Phase 1b/2a). In phase 1a (the dose escalation part), participants who have previously treated, histologically confirmed, unresectable advanced/metastatic solid tumors will be enrolled to determine the maximum tolerated dose and/or the recommended phase 2 dose (RP2D). Approximately six ascending dose levels of DB-1419 (accelerated titration design for the first dose level and “3+3” design for other dose levels) will be administrated by intravenous infusion. When a dose level is confirmed to be safe by the Safety Monitoring Committee (SMC), backfill participants may be enrolled to further evaluate the safety, tolerability, preliminary efficacy, and PK characteristics. Phase 1b/2a (the dose expansion part) will initiate with selected indications (e.g., small cell lung cancer [SCLC], hepatocellular cancer, and non-small cell lung cancer) randomized to one of two different dose levels for dose optimization. Five other cohorts will enroll participants with melanoma, esophageal squamous cell carcinoma, triple-negative breast cancer, extensive-stage SCLC who have received 4 cycles of first-line induction therapy without disease progression, and other solid tumors to further assess the safety and tolerability, antitumor activity, and other exploratory endpoints of DB-1419. The study is currently open in multiple centers and is on recruiting. As of Dec 05, 2024, four participants have been enrolled in Australia and the United States. Enrollment in China is scheduled to commence in March 2025. Citation Format: Shun Lu, Charlotte Lemech, Afaf Abed, John Powderly, Stephen V. Liu, Ziming Li, Li Jiang, Wei Gu, Qiqi Liu, Lianghua Fang, Yang Qiu, Rong Shi, Yujie Liu. A phase 1/2a, multicenter, open-label, first in human study of a bispecific ADC targeting B7H3 and PDL1 (DB-1419) in advanced or metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT121.

Byzantine broadcast is one of the fundamental problems in distributed computing. Many of its practical applications, from multiparty computation to consensus mechanisms for blockchains, require increasingly weaker trust assumptions, as well as scalability for an ever-growing number of users n. This rules out existing solutions which run in a linear number of rounds in n or rely on trusted setup requirements. In this paper, we propose the first sublinear-round and trustless Byzantine broadcast protocol for the dishonest majority setting. Unlike previous sublinear-round protocols, our protocol assumes neither the existence of a trusted dealer who honestly issues keys and correlated random strings to the parties nor random oracles. Instead, we present a solution whose setup is limited to an unstructured uniform reference string and a plain public key infrastructure (a.k.a. bulletin-board PKI).

3023 Background: DB-1303 is an antibody-drug conjugate (ADC) consisting of a humanized anti-HER2 IgG1 monoclonal antibody, covalently linked to proprietary DNA topoisomerase I inhibitor (P1003) via a maleimide tetrapeptide-based cleavable linker, with a high drug-to-antibody ratio (~8). Methods: This is a global first-in-human, dose-escalation and -expansion study in patients (pts) with advanced/metastatic solid tumors. Pts (ECOG 0-1) with HER2 – (high or low) expressing or mutant cancers who failed previously systemic therapies were recruited and received DB-1303 intravenously Q3W as monotherapy. The objectives were safety, tolerability, maximum tolerated dose (MTD) or recommended phase 2 dose (PR2D), pharmacokinetics (PK), and preliminary antitumor activity. Here we report the results from dose-escalation. Results: As of Jan 13, 2023, 85 pts received DB-1303 at 6 dose levels (2.2, 4.4, 6.0, 7.0, 8.0, and 10.0 mg/kg) and received a median of 7 (range, 1-27) prior lines of therapy, including previous anti-HER2 ADC therapy in 32.9% of pts. The median duration of treatment was 63.0 (range, 21-211) days, and 68 pts (80.0%) remained on treatment. Treatment-emergent adverse events (TEAEs) and ≥ grade (G) 3 TEAEs occurred in 74 pts (87.1%) and 18 pts (21.2%), respectively; the most common TEAEs were nausea (51.8%, 3.5% ≥ G3), vomiting (43.5%, 1.2% ≥ G3), platelet count decreased (35.3%, 3.5% ≥ G3), and anemia (29.4%, 5.9% ≥ G3). Few pts experienced neutropenia (10 [11.8%]) and alopecia (3 [3.5%]). There was no DLT or TEAEs leading to death. Interstitial lung disease occurred in 2 pts (2.4%, G1), without any ≥ G2. The exposure parameters (Cmax and AUC) of DB-1303 ADC increased with ascending doses from 2.2 to 10.0 mg/kg. The half-life of DB-1303 ADC is approximately 6-7 days for 6.0-8.0 mg/kg dose cohorts. The exposure of serum release payload was magnitudes lower than that of DB-1303 ADC, demonstrating stability of the ADC in systemic circulation. A total of 52 pts had undergone at least one post-baseline tumor scan. Twenty-three pts (44.2%, 23/52) had objective partial tumor response per RECIST 1.1: Thirteen HER2+ breast cancer (BC) (50.0%, 13/26, including 5 pts with brain metastases [55.6%, 5/9]), 5 HER2 low BC (38.5%, 5/13), 2 colorectal cancer (66.7%, 2/3), 1 endometrial carcinoma (33.3%, 1/3), 1 esophageal cancer (50.0%, 1/2), and 1 ovarian cancer (50.0%, 1/2). Among all the pts, the DCR was 88.5% (46/52); for pts with HER2+ BC and HER2-low BC, the DCRs were 96.2% (25/26) and 84.6% (11/13), respectively. Conclusions: DB-1303 was well tolerated with encouraging preliminary antitumor activity in heavily pretreated pts with advanced/metastatic solid tumors, especially in pts with HER2+ BC and brain metastasis as well as in HER2-low BC. Expansion is ongoing in selected tumor pts treated at the RP2D. Clinical trial information: NCT05150691 .

Ring-Learning-with-Errors (RLWE) has emerged as the foundation of many important techniques for improving security and privacy, including homomorphic encryption and post-quantum cryptography. While promising, these techniques have received limited use due to their extreme overheads of running on general-purpose machines. In this paper, we present a novel vector Instruction Set Architecture (ISA) and microarchitecture for accelerating the ring-based computations of RLWE. The ISA, named B512, is developed to meet the needs of ring processing workloads while balancing high-performance and general-purpose programming support. Having an ISA rather than fixed hardware facilitates continued software improvement post-fabrication and the ability to support the evolving workloads. We then propose the ring processing unit (RPU), a high-performance, modular implementation of B512. The RPU has native large word modular arithmetic support, capabilities for very wide parallel processing, and a large capacity highbandwidth scratchpad to meet the needs of ring processing. We address the challenges of programming the RPU using a newly developed SPIRAL backend. A configurable simulator is built to characterize design tradeoffs and quantify performance. The best performing design was implemented in RTL and used to validate simulator performance. In addition to our characterization, we show that a RPU using 20.5mm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> of GF12nm can provide a speedup of 1485× over a CPU running a 64k, 128-bit NTT, a core RLWE workload.

The 10th Workshop on Encrypted Computing and Applied Homomorphic Cryptography is held in Los Angeles, CA, USA on November 7, 2022, co-located with the ACM Conference on Computer and Communications Security (CCS). The workshop aims to bring together professionals, researchers and practitioners from academia, industry and government in the area of computer security and applied cryptography with an interest in practical applications of homomorphic encryption, encrypted computing, functional encryption and secure function evaluation, private information retrieval and searchable encryption. The workshop will feature 6 exciting accepted talks on different aspects of secure computation and a forum to discuss current and future challenges. Additionally, the workshop will feature one keynote presentation, as well as a working session. The complete WAHC'22 workshop proceedings are available at: https://dl.acm.org/doi/proceedings/10.1145/3560827.

e18725 Background: Healthcare data sharing is important for the creation of diverse and large data sets, supporting clinical decision making, and accelerating efficient research to improve patient outcomes. This is especially vital in the case of real world data analysis. However, stakeholders are reluctant to share their data without ensuring patients’ privacy, proper protection of their data sets and the ways they are being used. Homomorphic encryption is a cryptographic capability that can address these issues by enabling computation on encrypted data without ever decrypting it, so the analytics results are obtained without revealing the raw data. The aim of this study is to prove the accuracy of analytics results and the practical efficiency of the technology. Methods: A real-world data set of colorectal cancer patients’ survival data, following two different treatment interventions, including 623 patients and 24 variables, amounting to 14,952 items of data, was encrypted using leveled homomorphic encryption implemented in the PALISADE software library. Statistical analysis of key oncological endpoints was blindly performed on both the raw data and the homomorphically-encrypted data using descriptive statistics and survival analysis with Kaplan-Meier curves. Results were then compared with an accuracy goal of two decimals. Results: The difference between the raw data and the homomorphically encrypted data results, regarding all variables analyzed was within the pre-determined accuracy range goal, as well as the practical efficiency of the encrypted computation measured by run time, are presented in table. Conclusions: This study demonstrates that data encrypted with Homomorphic Encryption can be statistical analyzed with a precision of at least two decimal places, allowing safe clinical conclusions drawing while preserving patients’ privacy and protecting data owners’ data assets. Homomorphic encryption allows performing efficient computation on encrypted data non-interactively and without requiring decryption during computation time. Utilizing the technology will empower large-scale cross-institution and cross- stakeholder collaboration, allowing safe international collaborations. Clinical trial information: 0048-19-TLV. [Table: see text]