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• W4308382093 abstract "<h3>Background</h3> Bispecific antibodies (BsAbs) are an important class of therapeutics for immune-oncology applications. T cell engagers (TCEs) target tumor-associated antigens and cytotoxic T cells to eradicate antigen-expressing tumor cells. Blinatumomab (CD19 X CD3 bispecific) is approved for CD19-positive B cell acute lymphoblastic leukemia,¹ but its toxicity may be limiting, with one-third of patients in the pivotal Phase 3 study requiring treatment interruption for adverse events.² TCEs for solid tumors have likewise demonstrated encouraging clinical efficacy but shown dose-limiting toxicities due to on-target/off-tumor effects^3,4 For instance, patients receiving solitomab (EpCAM X CD3 bispecific) experienced severe gastrointestinal toxicity which precluded its further development.⁵ To minimize the off-tumor effects, we have developed ON-BOARD, an ultra-pH sensitive nanoparticle platform, has shown utility in cytokine and monoclonal antibody encapsulation and targeted delivery to the acidic tumor microenvironment.^6,7 The clinical safety and feasibility of ON-BOARD has been demonstrated by effective delivery of fluorophores to solid tumors for imaging of multiple tumor types in Phase I and II clinical trials with pegsitacianine.⁸ Herein we expand the utility of ON-BOARD platform for the encapsulation and pH-specific activation of bispecific antibodies with potential for anticancer therapy. <h3>Methods</h3> A panel of BsAbs (including biosimilar equivalents of blinatumomab, solitomab, and others) was used to demonstrate encapsulation by the ON-BOARD platform and pH-dependent activation. Formulations of ON-BOARD with BsAbs were purified by size exclusion chromatography and the encapsulation efficiencies were quantified by HPLC. Particle size and uniformity were studied by dynamic light scattering. ON-BOARD/BsAb formulations were assessed <i>in vitro</i> under neutral pH or acid-activated conditions to determine target engagement by ELISA, bio-layer interferometry. The target-specific bioactivity and therapeutic window was determined by TDCC assays in multiple models. <h3>Results</h3> ON-BOARD nanoparticles successfully encapsulated bispecific antibodies across a wide range of tumor-associated antigens (TAAs), including HER2, EpCAM, CEACAM5, CD19, and CD20, and structural configurations (tandem scFv and Fc-fusion). ON-BOARD formulations were stable nanoparticles with narrow size distribution (<70 nm), good encapsulation efficiency (up to 98%) and drug loading (up to 8%). Acid-mediated release and target engagement of both TAA-targeting and CD3-targeting arms was demonstrated using <i>in vitro</i> binding assays with >100-fold activation window. Further pH-specific cell killing was confirmed by TDCC assays in multiple <i>in vitro</i> models including Burkitt lymphoma, breast cancer, colorectal cancer, and lung cancer. <h3>Conclusions</h3> The ON-BOARD pH-sensitive nanoparticle platform demonstrated potential as an effective and universal tool for solid tumor specific activation and delivery of bispecific antibody therapeutics, potentially minimizing systemic side effects. <h3>References</h3> Goebeler ME, Bargou R. T cell-engaging therapies — BiTEs and beyond.<i> Nat Rev Clin Oncol</i> 2020;<b>17</b>:418–34. Kantarjian H, <i>et al</i>. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. <i>N Engl J Med</i> 2017;<b>376</b>:836–847. Zhou S, Liu M, Ren F, Meng X, Yu J. The landscape of bispecific T cell engager in cancer treatment. <i>Biomark Res.</i> 2021;<b>9</b>:38. Edeline J, Houot R, Marabelle A, Alcantara M. CAR-T cells and BiTEs in solid tumors: challenges and perspectives. <i>J Hematol Oncol</i>. 2021;<b>14</b>:65. Kebenko M, <i>et al</i>. A multicenter phase 1 study of solitomab (MT110, AMG 110), a bispecific EpCAM/CD3 T-cell engager (BiTE®) antibody construct, in patients with refractory solid tumors. <i>OncoImmunology</i> 2018;<b>7</b>:8. Ding X, Miller J, Su Q, <i>et al</i>. ONM-400, a novel approach for interleukin-2 therapy using a ph-activated nanoparticle targeting metabolic acidosis in solid cancers. <i>J Immunother Cancer</i> 2020;<b>8</b>(Suppl 3) A345. Bharadwaj G, Su Q, Gutowski S, <i>et al</i>. Encapsulating therapeutic antibodies for tumor specific activation and delivery using a clinically validated pH-sensitive nanoparticle platform. <i>Cancer Res</i> 2022;<b>82</b>(12_Supplement):1734. Voskuil FJ, Steinkamp PJ, Zhao T, <i>et al</i>. Exploiting metabolic acidosis in solid cancers using a tumor-agnostic pH-activatable nanoprobe for fluorescence-guided surgery.<i> Nat Commun</i>. 2020;<b>11</b>:3257." @default.
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• W4308382093 date "2022-11-01" @default.
• W4308382093 modified "2023-09-25" @default.
• W4308382093 title "1200 A clinically validated pH-sensitive nanomedicine platform for encapsulating therapeutic bispecific T cell engagers for tumor specific delivery and activation" @default.
• W4308382093 doi "https://doi.org/10.1136/jitc-2022-sitc2022.1200" @default.
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