enoblituzumab (MGA271)

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.

P2, N=33, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Jun 2024 --> Dec 2024

P2, N=0, Withdrawn, TJ Biopharma Co., Ltd. | N=160 --> 0 | Trial completion date: Dec 2024 --> Dec 2023 | Suspended --> Withdrawn | Trial primary completion date: Jun 2024 --> Dec 2023

P2, N=33, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Sep 2023 --> Jun 2024

P2, N=219, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Not yet recruiting --> Recruiting

P1, N=33, Suspended, Masonic Cancer Center, University of Minnesota | Recruiting --> Suspended

Particularly promising treatments are enoblituzumab for prostate cancer, 131I-omburtamab for central nervous system malignancies, and HS-20093 for small-cell lung cancer but further studies are warranted. These data will be telling of the efficacy of B7-H3 inhibitors in both hematologic and solid malignancies. This study aimed to compile available results of B7-H3 inhibitors in oncology clinical trials.

Multiple anti-B7-H3 therapies has been raised, such as DS-7300, MGA271, MGD009, and B7-H3 chimeric antigen receptor T-cell immunotherapy (CAR-T)...In the durvalumab-dependent cohort, paclitaxel-dependent cohort, anthracycline-dependent cohort, and our recruited NAT cohort, the B7-H3highPDL1low subgroup exhibited the lowest therapeutic response. Overall, this research provides a novel subtyping strategy based on the combination of B7-H3/PD-L1 expression that could potentially be applied to predict the therapeutic responses in TNBC, and suggests a potential biomarker-guided anti-B7-H3 therapy. Based on the classifier, we can select potential beneficiaries to deliver personalized medical services.

P2, N=219, Not yet recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Epitope mapping revealed non-overlapping B7-H3 binding epitopes of 6B5 and Enoblituzumab. Taken together, these data suggest that 6B5 is a promising therapeutic anti-human B7-H3 IgG monoclonal antibody that may find clinical application in a range of cancers, including current refractory types.

P2, N=160, Suspended, I-Mab Biopharma Co. Ltd. | Initiation date: Dec 2022 --> Dec 2023 | Not yet recruiting --> Suspended

In addition to its role in immune modulation, B7-H3 also promotes pro-tumorigenic functions such as tumor migration, invasion, metastases, resistance, and metabolism. In this review, we will provide an overview of this newly characterized immune checkpoint molecule and its development in the management of metastatic NSCLC.

P2, N=33, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Sep 2022 --> Jul 2023

P2, N=62, Terminated, MacroGenics | Trial completion date: Apr 2024 --> Jul 2022 | Recruiting --> Terminated | Trial primary completion date: Apr 2024 --> Jul 2022; Based on internal review of safety data

Results In preclinical studies, these multi-functional B7-H3 single-domain/1XX iPSC-derived CAR-T cells demonstrated improved tumor control compared to MGA271-scFv/1XX CAR-T cells...Conclusions Taken together, these results provide a tantalizing outlook for the effectiveness of multiplexed-engineered, iPSC-derived CAR-T cells targeting B7-H3, including in combination with therapeutic antibodies, for off-the-shelf treatment of solid tumors. Ethics Approval All animal experiments were reviewed and approved by Fate Therapeutics Animal Care Committee (IACUC) under the protocol 2019-11-01 O’Rouke.

P2, N=33, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Jul 2022 --> Sep 2022

P2, N=160, Not yet recruiting, I-Mab Biopharma Co. Ltd. | Initiation date: May 2022 --> Dec 2022

Canine CARs specific for B7-H3 were constructed using a single-chain variable fragment derived from the human B7-H3-specific antibody MGA271, which we confirmed to be cross-reactive with canine B7-H3...Safety of the CAR T cells were confirmed in two purposely bred healthy canine subjects following lymphodepletion by cyclophosphamide and fludarabine...The treatment regimen that we designed was confirmed to be safety in vivo. Our research provides a promising direction to establish in vitro and in vivo models for immunotherapy for canine and human solid tumor treatment.

P2, N=160, Not yet recruiting, I-Mab Biopharma Co. Ltd.

Checkpoint targeting with enoblituzumab and pembrolizumab demonstrated acceptable safety and antitumor activity in patients with CPI-naïve HNSCC and NSCLC.

Our data confirm the immunosuppressive function of B7H3 and demonstrate the immunoregulatory function of TJ271 as evidenced by the activation of cytolytic T cell and NK cells, reinvigoration of exhausted cells, and suppression of M2-like myeloid cells. These findings provide rationale for combination therapy with blockade of B7-H3 by TJ271 with other immunotherapies to achieve increased clinical efficacy against cancers.

The expression of CD276 showed a weak but statistically significant positive correlation with tumor diameter, but we did not find a significant association between CD276 expression and other histopathological clinical factors, or the response to initial therapy. A search of published data identified the monoclonal antibody (inhibitor) enoblituzumab as a potential drug for patients diagnosed with MTC overexpressing CD276.

P1, N=145, Completed, MacroGenics | Active, not recruiting --> Completed | Trial completion date: Oct 2022 --> Aug 2021

PD-L3 is a promising target for emerging drug enoblituzumab... Our study demonstrates that PD-L3 is expressed in the majority of MBC, indicating a possible role of anti–PD-L3 drugs. In MBC, PD-L3 exhibited high levels of expression in both metaplastic and epithelial components of the tumor. PD-L1 is expressed in a smaller fraction of MBC than PD-L3.

P2, N=33, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial completion date: Oct 2021 --> Jul 2022

In this neoadjuvant trial, inhibition of B7-H3 with enoblituzumab demonstrated favorable safety and encouraging activity in prostate cancer patients. Preliminary data suggest robust intratumoral induction (adaptive upregulation) of immune checkpoints, T cell activation, and myeloid inflammation.

P1, N=145, Active, not recruiting, MacroGenics | Trial primary completion date: Oct 2020 --> Oct 2021

We are developing therapeutics targeting B7-H3, including enoblituzumab, an Fc-engineered anti-B7-H3 monoclonal antibody, and MGC018, a duocarmycin-based B7-H3 ADC, both of which are currently being evaluated in clinical studies. B7-H3 is frequently overexpressed in SCCHN. At clinically relevant dose levels, MGC018 demonstrated potent antitumor activity in vivo toward SCCHN CDX mouse models and the majority of SCCHN PDX mouse models examined. These results support SCCHN as a potential indication that may be responsive to ADC-based treatments directed toward B7-H3.

P2, N=80, Recruiting, MacroGenics | Not yet recruiting --> Recruiting

P2, N=80, Not yet recruiting, MacroGenics

P2, N=33, Active, not recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Trial primary completion date: Nov 2020 --> Aug 2020

P2/3, N=0, Withdrawn, MacroGenics | N=750 --> 0 | Trial completion date: Oct 2025 --> Oct 2022 | Not yet recruiting --> Withdrawn | Trial primary completion date: Oct 2025 --> Oct 2020