A5038556121- Cancer Immunotherapy and Biomarkers
- Immune Cell Function and Interaction
- CAR-T cell therapy research
- IL-33, ST2, and ILC Pathways
- Monoclonal and Polyclonal Antibodies Research
- Immunotherapy and Immune Responses
- Biosimilars and Bioanalytical Methods
Atara Biotherapeutics (United States)
2022-2023
Pfizer (United States)
2021
Abstract IL2 signals pleiotropically on diverse cell types, some of which contribute to therapeutic activity against tumors, whereas others drive undesired activity, such as immunosuppression or toxicity. We explored the theory that targeting CD8+ T cells, are key antitumor effectors, could enhance its index. To this aim, we developed AB248, a CD8 cis-targeted demonstrates over 500-fold preference for cells natural killer and regulatory (Tregs), may toxicity immunosuppression, respectively....
Abstract The use of cytokines for immunotherapy shows clinical efficacy but is frequently accompanied by severe adverse events caused excessive and systemic immune activation. Here, we set out to address these challenges engineering a fusion protein single, potency-reduced, IL15 mutein PD1-specific antibody (anti-PD1-IL15m). This immunocytokine was designed deliver PD1-mediated, avidity-driven IL2/15 receptor stimulation PD1+ tumor-infiltrating lymphocytes (TIL) while minimally affecting...
Determine the differential effect of a FcγR-binding, mIgG2a anti-GITR antibody in mouse tumor models, and characterize microenvironment for frequency GITR expression T-cell subsets from seven different human solid tumors.Experimental Design: For experiments, wild-type C57BL/6 mice were subcutaneously injected with MC38 cells or B16 cells, BALB/c CT26 cells. Mice treated anti-mouse agonist 21B6, burden survival monitored. was evaluated at single-cell level using flow cytometry (FC). A total...
<h3>Background</h3> High-dose IL-2 induces complete responses in a subset of cancer patients, but severe toxicity, including vascular leak syndrome (VLS), limits its clinical potential. Insights into IL2Rα9s role the development VLS sparked wave second-generation molecules referred to as "not-α" IL-2s. Emerging data suggests that although not-α IL-2s avoid VLS, they induce suboptimal monotherapy activity patients. Given observation CD8+ T cells are dominant effector with IL-2-based...
<h3>Background</h3> AB248 is a fusion of an affinity-attenuated IL-2 mutein and antibody targeting CD8+ T cells designed to overcome the limitations wild-type second-generation IL-2Rβγ agonists, "not-α" IL-15 variants. Like IL-2, AB248's does not bind IL-2Rα thus avoids IL-2Rα-associated vascular leak syndrome (VLS) preferential Treg activation in nonclinical models. Further, has reduced IL-2Rβ affinity, its cis-targeting enables avoid biased expansion IL-2Rβ<sup>high</sup> NK...
<div>Abstract<p>IL2 signals pleiotropically on diverse cell types, some of which contribute to therapeutic activity against tumors, whereas others drive undesired activity, such as immunosuppression or toxicity. We explored the theory that targeting IL2 CD8<sup>+</sup> T cells, are key antitumor effectors, could enhance its index. To this aim, we developed AB248, a CD8 <i>cis</i>-targeted demonstrates over 500-fold preference for cells natural killer and...
<div>Abstract<p>IL2 signals pleiotropically on diverse cell types, some of which contribute to therapeutic activity against tumors, whereas others drive undesired activity, such as immunosuppression or toxicity. We explored the theory that targeting IL2 CD8<sup>+</sup> T cells, are key antitumor effectors, could enhance its index. To this aim, we developed AB248, a CD8 <i>cis</i>-targeted demonstrates over 500-fold preference for cells natural killer and...
<p>Supplementary Figure S8: Differential expression by treatment.</p>
<p>Supplementary Figure S10: In vitro and in vivo activity of AB248 cynomolgus monkey.</p>
<p>Supplementary Figure S5: Anti-tumor activity of CD8-mIL2 in combination with anti-PD-1 B16F10, 1956, MCA-205, and KP.mLama4 tumor models.</p>
<p>Supplementary Figure S3: Biodistribution of cytokine fusion molecules in tumor-bearing mice.</p>
<p>Supplementary Figure S9: scRNAseq analysis of MC38 tumors.</p>
<p>Supplementary Figure S4: Further characterization of CD8-mIL2 activity in mouse tumor models.</p>
<p>Supplementary Figure S2: In vitro culture of human CD8+ T cells, evaluation CD8α and CD8β expression, cytokine release assessment.</p>
<p>Supplementary Figure S5: Anti-tumor activity of CD8-mIL2 in combination with anti-PD-1 B16F10, 1956, MCA-205, and KP.mLama4 tumor models.</p>
<p>Supplementary Figure S4: Further characterization of CD8-mIL2 activity in mouse tumor models.</p>
<p>Supplementary Figure S1: CD8+ T cells drive anti-tumor activity but NK are responsible for toxicity with not-α-IL2 therapy.</p>
<p>Supplementary Figure S6: Characterization of antigen-specific CD8+ T cells in MC38 tumors.</p>
<p>Supplementary Figure S10: In vitro and in vivo activity of AB248 cynomolgus monkey.</p>