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ISB 1442 is a bispecific antibody (BsAb) using Ichnos' proprietary Bispecific Engagement by Antibodies based on the T-cell receptor (BEAT ®) platform. A fully human BsAb with anti-CD38 and CD47 binding arms, ISB 1442 was developed for the treatment of relapsed/refractory multiple myeloma (rrMM). The CD38 binding arm consists of two bi-paratopic Fabs that strongly bind to CD38 through avidity-induced interactions. The anti-CD47 arm comprises a single Fab arm designed to block the interaction between CD47 and the signal-regulatory protein alpha (SIRPα) receptor present on phagocytes (including macrophages, monocytes and dendritic cells). With this design, the CD38 Fab arm preferentially drives binding to tumor cells and enables blocking of proximal CD47 receptors on the same cell via avidity-induced binding. Hence, ISB 1442 is anticipated to induce minimal unintended effects on red blood cell (RBC) hemagglutination compared to benchmark anti-CD47 monoclonal antibodies (mAb) magrolimab. The Fc portion of ISB 1442 is engineered to enhance antibody dependent cell phagocytosis (ADCP), antibody dependent cell cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC). ISB 1442 is the first-in-class with these unique molecular attributes, which are designed to overcome mechanisms of resistance to daratumumab in rrMM patients. In vitro, ISB 1442 exhibited a higher killing potency compared to benchmark daratumumab across a broad range of CD38-expressing tumor cells. Specifically, ISB 1442 showed a high potency to kill CD38 high tumor cells through CDC and a superior potency to kill CD38 low expressing tumor cells through ADCC and ADCP compared to daratumumab. Additionally, ISB 1442 showed in vitro tumor killing potency through phagocytosis comparable to magrolimab, an anti-CD47 mAb (IgG4) acting mostly through ADCP. Consistent with its molecular design, which includes a functional Fc, ISB 1442 induced more potent killing of CD38 high and CD38 low tumor cells by CDC and ADCC compared to magrolimab. To characterize the complex mechanisms of action of ISB 1442 in a single system more fully, a multiple mode of action of killing (MMoAK) in vitro assay was established where autologous macrophages and PBMCs from healthy donors were incubated with CD38 low expressing tumor cells and human serum. With this approach, tumor cells can be targeted simultaneously by NK cells from PBMCs, autologous macrophages, and complement from human serum. In MMoAK, ISB 1442 exhibited prominent tumor cell killing that was twice as high as daratumumab. The presence of soluble CD38 or RBCs, the main source of antigen sinks for CD38 and CD47, did not affect the killing potency of ISB 1442 across in vitro assays using CD38 high or CD38 low expressing tumor cells. These data suggest that the molecular design of ISB 1442 mitigates the potential risk of CD47 and CD38 antigen sink and the related side effects. On-target specificity was evaluated in vitro by measuring binding to human RBCs, induction of hemagglutination and RBC depletion, hemolysis and platelet aggregation. ISB 1442 did not cause any detectable hemolysis, RBC depletion or platelet aggregation in vitro and showed a marked reduction in human RBC hemagglutination relative to magrolimab, suggesting a more favorable on-target specificity profile. Finally, the potency of ISB 1442 was assessed in vivo in a therapeutic model of subcutaneously established Raji tumor xenograft in CB17/SCID mice which have functional complement, macrophages and NK cells of murine origin. ISB 1442 induced higher tumor growth inhibition relative to daratumumab and comparable tumor regression compared to magrolimab. In summary, we report a novel approach for the treatment for rrMM by co-targeting CD38 and CD47 using a 2+1 biparatopic bispecific antibody. Based on its unique design and multiple mechanisms of action, ISB 1442 is anticipated to enhance antitumor activity in rrMM patients relative to anti-CD38 mAbs by overcoming primary and acquired tumor escape mechanisms of resistance. Disclosures No relevant conflicts of interest to declare.

and as Standardized Response Mean (SRM; mean score change divided by change standard deviation). Effect sizes were categorized as small 0.20e0.49, moderate 0.50e0.79 or large !0.8. Results: Complete longitudinal data for all three measures at all three time points were available for 2904 patients (75% women, mean age 64.2 years, mean BMI 27.8). The effect sizes for the physical component score of SF-12, the SF-6D and for the EQ-5D index at both 3 and 12 months were similar and around 0.4, Figure 1. The effect sizes for the mental component score of SF-12 and the EQ VAS were lower and around 0.1e0.2, Figure 1. The effect size for the pain VAS was higher at both time points and approaching 0.6. Mean values, ESs and SRMs for all three instruments are given in Table 1. Conclusions: In this head-to-head comparison, we found SF-12 PCS, SF-6D and EQ-5D to be similarly responsive at both 3 and 12 months. The physical component score of SF-12, SF-6D and the EQ-5D index were the more responsive measures, with effect sizes categorized as small. Both generic measures were sensitive to change over time, and hold the potential for evaluation of change in overall health status and for use in health economic evaluations following combined patient education and supervised exercise in patients with knee or hip OA.

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The authors developed and evaluated a transdermal gel formulation of ketorolac tromethamine (ketorolac) for the treatment of nociceptive somatic pain. The formulation was optimized for skin permeation enhancers, pH of the system, and dosage strength using in vitro and in vivo techniques. Of the various permeation enhancers evaluated, dimethyl sulfoxide (DMSO) and oleic acid were found to significantly increase skin permeation flux of ketorolac. The concentration of DMSO affected the rate as well as extent of transdermal absorption. Use of citric acid further improved the skin penetration of ketorolac. In vitro diffusion results indicated significant increase in drug permeation with increasing drug concentration. However, the same did not translate into higher skin permeation during in vivo study. Although the area under concentration time curve (AUC(0-t)) increased significantly with increasing dose, the effect on maximum serum concentration (C(max)) was insignificant. The formulation can be used for inflammatory pain management while avoiding gastric adverse events associated with oral ketorolac.