717 - Clinical efficacy, safety, and pharmacokinetic profile of bosakitug (BSI-045B), an anti-thymic stromal lymphopoietin (TSLP) mAb in a phase 2 study of moderate and severe atopic dermatitis subjects

Author: Davis, Hugh M ; Zhang, Jing ; Liu, Xiaodong F ; Zhang, Chu ; Yu, Qinghua ; Chen, Mingjiu ; Teng, Shu-Wen ; Appel, James E ; Parish, Jennifer L ; Silverberg, Jonathan I

AbstractIntroduction/BackgroundBosakitug (BSI-045B) is a humanized monoclonal antibody targeting thymic stromal lymphopoietin (TSLP) which is a master regulator of type 2 (Th2) immune responses at the barrier surfaces of skin and the respiratory/gastrointestinal tract. The expression of TSLP is elevated in individuals with atopic diseases such as atopic dermatitis (AD). Herein, we describe the clinical efficacy, safety, and pharmacokinetic results of bosakitug from a phase 2a study in moderate to severe AD subjects (ADAMANT).ObjectivesTo evaluate the safety, clinical efficacy, pharmacokinetic characteristics, and immunogenicity (ADA) of monotherapy bosakitug injection in AD subjects.MethodsEach enrolled AD subject received 300 mg of bosakitug subcutaneous injection weekly for 4 weeks and then every 2 weeks thereafter through 23 weeks of treatment. Following the treatment phase, subjects are followed for 12 weeks. Eczema Area and Severity Index (EASI), Investigator’s Global Assessment (IGA), and Peak Pruritus Numerical Rating Scale (PPNRS) score were measured at baseline and at each study visit to assess clinical efficacy. Pharmacokinetic, pharmacodynamic, and ADA samples were collected at pre-dose, at each study visit and, if necessary, at the time of early withdrawal of study drug.ResultsTwenty-two subjects with moderate and severe disease were enrolled into the trial. Baseline mean scores for the cohort were EASI of 17.5, IGA of 3.05, and PP-NRS of 6.5. At week 23, with 18 evaluable participants completing the dosing phase of the study, 79% of the AD subjects achieved an IGA 0/1, 89% achieved an EASI-75, 44% achieved an EASI-90 and 28% achieved an EASI-100. The mean PP-NRS score decreased by ∼3 points through the end of the dosing period. The mean percentage change from baseline in EASI score showed continual improvement beyond week 23. By week 31, the five subjects who had reached eight weeks following their last dose, exhibited an EASI score reduction of 93% from baseline. One subject became pregnant after 7 doses at which time drug treatment was discontinued. The individual had already attained a 98% response in EASI score at that time. After 6 months post treatment the individual continues to maintain bosakitug exposure and an EASI response of 82%. A summary of the safety profile of bosakitug includes 19 AEs in 9 subjects during study treatment, all were of grade 1 except one of vertigo (grade 2); 16 subjects reported injection site reactions; and headache was the most common AE (4 cases in 4 subjects). No SAEs occurred. None of the 22 subjects exhibited a positive ADA response.ConclusionsThe efficacy profile exhibited by bosakitug, with 79% of AD subjects achieving an IGA 0 or 1 and almost 90% of subjects showing 75% skin clearance is quite striking, especially as monotherapy. The 44 and 28% of subjects that achieved EASI-90 and EASI-100, respectively, also shows the high efficacious potential of bosakitug. In this phase 2a proof-of-concept study the dosing regimen was chosen to mimic the dupilumab dosing regimen in AD subjects to be able to compare efficacy and safety directly. Bosakitug’s substantially higher efficacy, as exhibited by 78% of subjects achieving an IGA 0/1, underscore its competitiveness to dupilumab and its potential as a first-in-class treatment for AD. The sustained concentration of bosakitug, due to its long half-life, and the continued efficacy after the last dose provides a good possibility that bosakitug could be administered at extended dosing intervals. Bosakitug’s impressive efficacy and safety profile, in conjunction with the opportunity for much longer dosing intervals than established therapies support further clinical development of bosakitug in a phase 2b, randomized, blinded, dose-finding trial in moderate to severe AD subjects.

22 Mar 2024·Cancer Research

Abstract 3135: BSI-730, a bispecific antibody targeting HER2 and PD-L1 for the development of a first-in-class bispecific ADC

Author: Davis, Hugh M. ; Lyu, Qun ; Chen, Mingjiu ; Liu, Jinyu ; Peng, Zeyu ; Dai, Wenwen ; Hu, Hui-Han ; Li, Hongyan ; Xia, Shukai ; Li, Jun ; Pan, Ying ; Liu, Xiaodong F. ; Hao, Xiaoyao

AbstractBackground: Antibody-drug conjugates (ADCs) have become a promising therapeutic option for patients with cancer. Bispecific ADCs targeting two tumor-associated antigens have potential differential anti-tumor advantages. HER2 and PD-L1 are co-expressed in some tumor cell types, such as breast cancer, gastric cancer, lung adenocarcinoma and urothelial carcinoma. A bispecific ADC targeting HER2 and PD-L1 should provide therapeutic benefit, particularly for patients with HER2 low cancer. Dual-target mediated cytotoxicity combined with PD-L1 mediated immunotherapy provides an innovative approach for cancer patients.Experimental procedures: An anti-PD-L1 monoclonal antibody was identified from A/J mice immunized with PD-L1-ECD-Fc and screened by the Biosion proprietary SynTracer® High Throughput Endocytosis Platform. A “knob-in-hole” bispecific antibody, BSI-730, targeting HER2 and PD-L1 was created with trastuzumab and the humanized anti-PD-L1 scFv. Target binding specificity, binding activity, and affinity of BSI-730 were evaluated by protein-based ELISA, cell-based FACS and Biacore-based SPR, and the ligand blocking activity of PD-L1 portion was measured by competitive ELISA and cell-based FACS. The internalization activities on various cancer cell lines with different expression levels of HER2 and PD-L1 were evaluated by using the SynTracer® Platform.Summary: BSI-730, a HER2/PD-L1 bispecific antibody, showed comparable binding affinity to HER2 as compared to trastuzumab, as well as comparable bioactivity to the parental anti-PD-L1 antibody regarding PD-L1 binding and PD-1/PD-L1 blocking. Based on a cell-based reporter assay, BSI-730 was able to reverse PD-L1 mediated T-cell suppression and exhibited comparable potency to the parental anti-PD-L1 antibody. The internalization of BSI-730 on HER2 low cancer cell lines was stronger than that of trastuzumab whereas the internalization of BSI-730 on HER2 high cancer cell lines was comparable to that of trastuzumab.Conclusion: BSI-730 is a novel bispecific antibody for the development of a first-in-class bispecific ADC with the potential advantage of increased potency that can be further investigated to treat HER2 and PD-L1 co-expression tumors, particularly HER2 low tumors.Citation Format: Xiaoyao Hao, Hongyan Li, Xiaodong F. Liu, Jinyu Liu, Wenwen Dai, Ying Pan, Hui-Han Hu, Jun Li, Shukai Xia, Qun Lyu, Hugh M. Davis, Mingjiu Chen, Zeyu Peng. BSI-730, a bispecific antibody targeting HER2 and PD-L1 for the development of a first-in-class bispecific ADC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3135.

22 Mar 2024·Cancer Research

Abstract 1343: BSI-111, a highly selective anti-CD16a monoclonal antibody with potent agonist activity for building a NK cell engager platform

Author: Davis, Hugh M. ; Liu, Jinyu ; Li, Hongyan ; Peng, Zeyu ; Lyu, Qun ; Chen, Mingjiu ; Dai, Wenwen ; Liu, Xiaodong F. ; Li, Jun ; Xia, Shukai

AbstractBackground: Natural killer cells (NK) are innate lymphocytes endowed with the ability to recognize and kill cancer cells. CD16a, a well-characterized activating receptor predominantly expressed on NK cells, is a low-affinity receptor for the IgG Fc domain and is crucial for stimulating NK cell-mediated tumor cell killing. Unlike CD16a, CD16b is mainly expressed on granulocytes as a GPI-anchored receptor and is not involved in the lysis of tumor cells although CD16a and CD16b share 97% sequence identity in their extracellular domains. Due to the high homology of extracellular domains of CD16a and CD16b, it is extremely challenging to develop CD16a-specific agonistic antibodies without binding CD16b+ granulocytes, the most abundant subset in leukocytes. Here we report the development of an anti-CD16a-specific monoclonal antibody with potent NK cell activation.Experimental procedures: Humanized mice were immunized with recombinant CD16a-ECD-Fc. The Biosion proprietary H3 (High-throughput, High-content and High-efficiency) antibody screening platform was used to identify an anti-CD16a monoclonal antibody lead candidate - BSI-111. The target binding specificity, binding activity, and affinity of BSI-111 were evaluated by protein-based ELISA, cell-based FACS and Biacore-based SPR. A cell-based agonist reporter assay and a primary NK cell activation assay were used to evaluate the bioactivity of BSI-111.Summary: BSI-111 is a fully human monoclonal antibody with the following critical properties: (1) specifically binds to CD16a without recognizing CD16b; (2) binds the two allelic variants of CD16A - 158F and 158V with similar high affinities; (3) shows cross-reactivity to cynomolgus CD16a; (4) can significantly activate NFAT signaling in a cell-based reporter assay; (5) exhibits strong activity on activating primary NK cells; and (6) has potentially longer half-life and silenced Fc-effector function through Fc-engineering.Conclusion: BSI-111 demonstrates great biophysical properties and functional characteristics, supporting the development of anti-CD16a-based NK cell engagers for potential benefit of cancer patients.Citation Format: Jinyu Liu, Wenwen Dai, Hongyan Li, Xiaodong F. Liu, Jun Li, Shukai Xia, Qun Lyu, Hugh M. Davis, Mingjiu Chen, Zeyu Peng. BSI-111, a highly selective anti-CD16a monoclonal antibody with potent agonist activity for building a NK cell engager platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1343.

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