enoblituzumab (MGA271) / MacroGenics - LARVOL DELTA

Neoadjuvant enoblituzumab in localized prostate cancer: a single-arm, phase 2 trial. (PubMed, Nat Med) - P2 | "The present study validates B7-H3 as a rational target for therapy development in PCa with larger studies planned. The ClinicalTrials.gov identifier is NCT02923180."

IO biomarker • Journal • P2 data • Genito-urinary Cancer • Immune Modulation • Oncology • Prostate Cancer • Solid Tumor

A CAR-T Tonic Signaling Code Predicts Anti-Tumor Efficacy in Diffuse Midline Glioma. (PubMed, Neuro Oncol) - "Our findings establish that scFv-dependent modulation of tonic signaling critically governs CAR-T persistence and antitumor efficacy in DMG. By linking CAR design to transcriptional and epigenetic programs, our study provides a principle-based and predictive framework to inform rational CAR engineering and improve therapeutic outcomes."

Journal • Brain Cancer • Diffuse Midline Glioma • Glioma • Oncology • Pediatrics • Solid Tumor • CD276

Neoadjuvant Enoblituzumab (MGA271) in Men With Localized Intermediate and High-Risk Prostate Cancer (clinicaltrials.gov) - P2 | N=33 | Active, not recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Jul 2026 ➔ Jul 2027

IO biomarker • Trial completion date • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor • PD-L1

Preclinical targeted alpha therapy of B7-H3-positive tumors using [225Ac]Ac-Macropa-PEG2-enoblituzumab via EDC/NHS-mediated conjugation. (PubMed, Int J Radiat Biol) - "Therapy studies demonstrated significant tumor growth inhibition and prolonged survival with good tolerability. [225Ac]Ac-Macropa-PEG2-Enoblituzumab shows strong stability, specificity, and therapeutic efficacy, supporting further development as a promising translational candidate for targeted alpha therapy of B7-H3-expressing malignancies."

Journal • Preclinical • Oncology • Solid Tumor • CD276

HEAT: Trial of Neoadjuvant Enoblituzumab vs SOC in Men With High-Risk Localized Prostate Cancer (clinicaltrials.gov) - P2 | N=219 | Active, not recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Recruiting ➔ Active, not recruiting

Enrollment closed • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor

Developability engineering of scFvs enables robust CAR function under transient mRNA expression. (PubMed, Sci Rep) - "For MGA271-derived binders, optimisation reduced non-specific interactions and off-target killing despite reduced monovalent affinity. Together, these data establish developability engineering of scFvs as a critical enabling step for transient mRNA-encoded CAR therapies."

IO biomarker • Journal

GPC3 chimeric antigen receptor (CAR)-NK cells combined with Enoblituzumab enhance the anti-tumor efficacy against hepatocellular carcinoma. (PubMed, Biochem Biophys Res Commun) - "Our findings demonstrate that dual targeting of GPC3 and B7H3 effectively enhances NK cell-mediated antitumor activity. This strategy leverages both CAR-mediated specificity and NK cell-intrinsic mechanisms, providing a strong rationale for developing dual-target immunotherapies to improve outcomes in HCC patients."

IO biomarker • Journal • Hematological Disorders • Hematological Malignancies • Hepatocellular Cancer • Oncology • Solid Tumor • CD276 • GPC3 • IFNG • LAMP1

Characterizing and optimizing EphA2-targeted CAR T-cells for Group 3 medulloblastoma therapy (ISPNO 2026) - "To contextualize our results, we compared EphA2-CAR T-cells with 4H5 scFv and CD28ζ signaling to clinically relevant B7-H3-CAR T-cells with MGA271 scFv and CD28ζ signaling. We show that genetic deletion of DNMT3A or Regnase-1, or expression of a constitutive active IL-18 receptor significantly enhanced in vivo efficacy, while MyD88.CD40 co-stimulation or expression of a constitutively active IL-2 receptor did not. Together, our results support continued clinical development of EphA2-targeted CAR T-cells for G3MB."

CAR T-Cell Therapy • IO biomarker • Brain Cancer • Medulloblastoma • Solid Tumor • CD276 • CD40 • DNMT3A • EPHA2 • IL18 • IL2 • MYD88

CYTOPLASMIC LOCALIZATION OF QKI MEDIATES THERAPUETIC RESISTANCE AND IMMUNE EVASION (EHA 2026) - "Genetic deletion of QKI sensitized AML cells to venetoclax alone and in combination with 5-azacytidine in vitro and in vivo. Targeting CD276 using the monoclonal antibody enoblituzumab demonstrated strong synergy with venetoclax in eliminating AML cells. . Summary/Conclusion These findings identify cytoplasmic QKI as a key regulator of differentiation-associated venetoclax resistance and immune evasion in AML and support targeting CD276 as a rational therapeutic strategy to overcome therapy resistance."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • CD276 • METTL1 • ZFP36 • ZFP36L1

Fluorescence-Guided Surgery of Rhabdomyosarcoma Using a B7-H3 Targeted Antibody-Fluorophore Conjugate. (PubMed, Mol Pharm) - "Collectively, these findings demonstrate that B7-H3-targeted NIRF imaging with MGA271-IRDye800 offers sensitive and specific intraoperative visualization of sarcoma. This probe demonstrates strong potential for clinical translation as a molecular imaging agent to guide surgical resection, reduce residual disease, and ultimately improve outcomes for patients with B7-H3-expressing sarcomas."

Journal • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor

Engineering functionality-optimized fully human B7-H3 CAR T cells for enhanced solid tumor therapy. (PubMed, Cell Rep Med) - "In pancreatic cancer, neuroblastoma, and glioblastoma xenograft models, CAR T cells incorporating the lead human binder Y111 are well tolerated and demonstrate superior antitumor activity compared with 376.96- and MGA271-based CARs. Y111 CAR treatment induces complete responses, tumor rejection, and significant survival benefits, identifying Y111 as a promising fully human B7-H3 CAR for solid tumors."

Journal • Brain Cancer • Glioblastoma • Neuroblastoma • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CD276

Internalization of B7-H3 is enhanced by cholesterol disruption in esophageal cancer cells (AACR 2026) - "While the pimitespib enhanced trastuzumab-mediated HER2 internalization, enoblituzumab-mediated B7-H3 internalization was not affected. These results suggest that membrane cholesterol, rather than HSP90, might affect the stability of B7-H3 on the cell membrane. In conclusion, membrane cholesterol disruption could enhance the internalization efficacy of HER2 and B7-H3 molecules."

Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • CD276 • CDC37 • HSP90AA1

pH/ROS-Responsive Injectable Hydrogel Co-Loaded with B7-H3 Blocker and NETs Suppressor Boosts OSCC Synergistic Immunotherapy. (PubMed, Adv Sci (Weinh)) - "This study presents an injectable pH/ROS-dual-responsive hydrogel co-loaded with enoblituzumab (B7-H3 blocker) and Cl-amidine (NETs suppressor)...The hydrogel exhibits excellent biocompatibility without systemic toxicity. This TME-responsive combination strategy offers a promising approach to enhance immunotherapy efficacy and overcome immune resistance in OSCC."

Journal • Oncology • Oral Cancer • Squamous Cell Carcinoma • CD276 • CD4 • CD8

Engineering Functionality Optimized fully human B7-H3 CAR T Cells for Enhanced Solid Tumor Therapy. (PubMed, bioRxiv) - "In pancreatic cancer, neuroblastoma, and glioblastoma xenograft models, CAR T cells incorporating the lead human binder Y111 were well tolerated and demonstrated superior antitumor activity compared with 376.96- and MGA271-based CARs. Y111 CAR treatment induced complete responses, tumor rejection, and significant survival benefits, identifying Y111 as a promising fully human B7-H3 CAR for solid tumors."

Journal • Brain Cancer • Glioblastoma • Neuroblastoma • Oncology • Pancreatic Cancer • Solid Tumor • CD276

FLT3/ITD-driven noncanonical STAT1 S727 phosphorylation upregulates CD276, mediating CD8positive- T cell exhaustion and immune evasion in AML (ASH 2025) - "Multipleximmunohistochemical confirmed elevated pS727-STAT1+CD276+ blasts and reduced CD8+ T cells inFLT3/ITD patient samples, linking FLT3/ITD–STAT1 signaling to CD276 transactivation and immunesuppression.Pharmacologic (fludarabine) and genetic approaches showed dose-dependent suppression of CD276mRNA and protein in FLT3/ITD models. In FLT3/ITDPDX models, quizartinib + MGA271/MG009 achieved a 99% complete remission rate, with excellenttolerability, validating CD276 blockade as a potent synergistic strategy with FLT3 inhibition.In summary, FLT3/ITD drives CD8+ T cell exhaustion via tumor-intrinsic CD276 upregulation, mediated bySTAT1 S727 phosphorylation. Co-targeting FLT3 and CD276 synergistically restores T-cell function anderadicates leukemia in vivo, offering a translatable immunotherapy strategy for AML."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • CD276 • CD8 • FLT3 • GZMB • IFNG • STAT1 • STAT5

Cytoplasmic localization of qki mediates therapeutic resistance and immune evasion (ASH 2025) - "The combination of the BCL2 inhibitor venetoclax with the hypomethylating agent 5-azacytidine hasrevolutionized AML treatment in older patients. Finally, we assessed the combination of venetoclax with enoblituzumab, a monoclonal antibodythat blocks CD276, which exhibited a strong synergistic effect in eliminating AML cells. This underscorescytoplasmic QKI localization as a key driver of venetoclax resistance through monocytic AMLdifferentiation and highlights a promising immune-based strategy to overcome this resistance."

IO biomarker • CD276 • METTL1 • ZFP36 • ZFP36L1

A Phase I, Open-Label, Dose Escalation Study of Enoblituzumab in Children and Young Adults with B7-H3-Expressing Relapsed or Refractory Solid Tumors. (PubMed, Cancer Res Commun) - "B7-H3 is expressed on a high proportion of pediatric solid tumors. While enoblituzumab could be safely administered at a weekly dose of 15 mg/kg, no objective tumor responses were observed. Alternative strategies to target B7-H3 in children with relapsed solid tumors should be considered."

Journal • Hypotension • Oncology • Pediatrics • Solid Tumor • CD276

Neoadjuvant Enoblituzumab (MGA271) in Men With Localized Intermediate and High-Risk Prostate Cancer (clinicaltrials.gov) - P2 | N=33 | Active, not recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Jul 2025 ➔ Jul 2026

IO biomarker • Trial completion date • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor • PD-L1

Identification of Hub Genes and Pathways in Preinfusion Chimeric Antigen Receptor (CAR) T-cell Products Associated With Cytokine Release Syndrome. (PubMed, Cureus) - " The study highlights IL1B, IL15, CD276, NCR2, and CCL17 as key CRS genes in preinfusion CAR T-cell products. Their dysregulation activity may contribute to the increased inflammation noted in CRS, pointing to a loss of regulatory control. Bringing us closer to better patient outcomes, these findings not only suggest that these genes could serve as valuable biomarkers for predicting CRS but also open the way for the development of more precise treatments such as combining drugs such as enoblituzumab and canakinumab, which might assist in reducing CRS severity and making CAR T-cell therapy safer and more effective, ultimately improving patient lives."

Journal • Inflammation • Oncology • CD22 • CD276 • IL15 • IL17A • IL1B

MT2021-27 FT538 Recurrent Ovarian, Fallopian Tube, and Primary Peritoneal Cancer (clinicaltrials.gov) - P1 | N=1 | Terminated | Sponsor: Masonic Cancer Center, University of Minnesota | N=33 ➔ 1 | Trial completion date: Sep 2028 ➔ Aug 2024 | Suspended ➔ Terminated | Trial primary completion date: Sep 2026 ➔ Aug 2024; Product withdrawn from clinical development

Enrollment change • Platinum resistant • Trial completion date • Trial primary completion date • Trial termination • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Peritoneal Cancer • Solid Tumor

Neoadjuvant Enoblituzumab (MGA271) in Men With Localized Intermediate and High-Risk Prostate Cancer (clinicaltrials.gov) - P2 | N=33 | Active, not recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Dec 2024 ➔ Jul 2025

IO biomarker • Trial completion date • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor • AR • CD276 • HAVCR2 • LAG3 • LAMP1 • PD-1 • TNFRSF9

Dual role of CD276 as target antigen and putative activation marker in CD276-redirected CAR T cells for the treatment of solid tumors (SITC 2024) - "Despite published CAR T cell therapies targeting CD276 (376.96, MGA271, and B12) and numerous ongoing clinical trials, the therapeutic benefits of these therapies remain underwhelming.1–3 The present study aims to develop novel, superior CAR constructs targeting human CD276 in solid tumors, and to investigate the putative role of CD276 as a T cell activating and modulatory molecule4–7 in the context of CD276-CAR-T cells...Conclusions The novel CD276-CAR-T cells CARs D0506 and D0537 maintained persistence and potent cytotoxicity upon long-term tumor cell re-challenge, concordantly with heightened CD276 surface expression during manufacturing and target-dependent activation. These findings point to CD276 as a putative activation marker and modulator of CAR-T cell function, and may inform further CD276 CAR engineering strategies."

CAR T-Cell Therapy • IO biomarker • Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • CD276 • CD4 • CD8 • IFNG • IL2 • TNFA

ITGB6 modulates resistance to anti-CD276 therapy in head and neck cancer by promoting PF4+ macrophage infiltration. (PubMed, Nat Commun) - "Enoblituzumab, an immunotherapeutic agent targeting CD276, shows both safety and efficacy in activating T cells and oligodendrocyte-like cells against various cancers...Further investigations demonstrate that inhibiting ITGB6 restores sensitivity to PD1 antibodies in mice resistant to anti-PD1 treatment. In summary, our research reveals a resistance mechanism associated with immune checkpoint inhibitor therapy and identifies potential targets to overcome resistance in cancer treatment."

IO biomarker • Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CD276 • CD8 • CX3CL1 • CX3CR1 • CXCL16 • CXCR6 • ITGB6

Neoadjuvant Enoblituzumab (MGA271) in Men With Localized Intermediate and High-Risk Prostate Cancer (clinicaltrials.gov) - P2 | N=33 | Active, not recruiting | Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Jun 2024 ➔ Dec 2024

IO biomarker • Trial completion date • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • AR • CD276 • HAVCR2 • LAG3 • LAMP1 • PD-1 • TNFRSF9

A phase 2 randomized trial of neoadjuvant enoblituzumab versus standard of care in men with high-risk localized prostate cancer: The help elucidate and attack longitudinally (HEAT) prostate cancer randomized study. (ASCO 2024) - P2 | "The primary endpoint is recurrence-free survival (RFS) defined as any metastasis events, local pelvic visceral or lymph node recurrence, detectable prostate-specific antigen (PSA), or start of subsequent local or systemic therapy (including salvage or adjuvant therapy), or death for any cause, whichever occurs first. Secondary endpoints include additional clinical and immunologic correlates."

Clinical • IO biomarker • P2 data • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • CD8 • PD-L1 • PD-L2