vobramitamab duocarmazine (MGC018)

P2, N=17, Recruiting, Georgetown University | Not yet recruiting --> Recruiting

P2, N=382, Active, not recruiting, MacroGenics | N=100 --> 382 | Trial completion date: Dec 2026 --> May 2027 | Trial primary completion date: Dec 2026 --> May 2027

P1, N=278, Recruiting, MacroGenics | Trial completion date: Mar 2025 --> Mar 2026 | Trial primary completion date: Mar 2024 --> Mar 2025

P2, N=17, Not yet recruiting, Georgetown University

P2, N=100, Active, not recruiting, MacroGenics

Vobra duo showed robust in vitro cytolytic activity against CD276 positive AML cells highlighting the need for ongoing preclinical evaluations of CD276 targeted therapies in AML. Given the established safety profile for vobra duo this provides a clear path for rapid translation to clinical use for high risk AML patients.

P2, N=100, Active, not recruiting, MacroGenics | Recruiting --> Active, not recruiting

Vobra duo exerts relevant antitumor activity in preclinical B7-H3-expressing NB models and represents a potential candidate for clinical translation.

The study will enroll participants with mCRPC previously treated with one prior ARAT (abiraterone, enzalutamide, or apalutamide) for prostate cancer. One futility analysis based on PSA50 response rate will be performed for each arm after 20 evaluable patients are enrolled. Enrollment is ongoing.

P2, N=100, Recruiting, MacroGenics | Phase classification: P2/3 --> P2 | N=420 --> 100

P1/2, N=143, Terminated, MacroGenics | Active, not recruiting --> Terminated; Business decision

In the pseudometastatic model and in five orthotopic NB mouse models, weekly iv treatments with 1 mg/kg MGC018 for 3 weeks resulted in delayed tumor growth and increased survival rates compared to animals treated with an irrelevant (anti-CD20) duocarmycin-ADC or an anti-GD2 antibody (dinutuximab beta). A 4-week course of treatment further ameliorated MGC018 antitumor effect in both the orthotopic and resected NB models and increased the survival of NB-bearing mice co-treated with TOpotecan-TEMozolomide (TOTEM), the standard-of-care therapy for relapsed disease. MGC018 exerts relevant antitumor activity in pre-clinical NB models and may represent a potential candidate for future NB clinical translation.

P1/2, N=143, Active, not recruiting, MacroGenics | Trial primary completion date: Mar 2023 --> Jun 2023

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.

P1/2, N=150, Active, not recruiting, MacroGenics | Recruiting --> Active, not recruiting

P1/2, N=182, Recruiting, MacroGenics | Trial completion date: May 2025 --> May 2023 | Trial primary completion date: Mar 2022 --> Mar 2023

Examine B7H3 as a target for an ADC with a duocarmycin payload Presenting a safety overview from Phase I Analyse efficacy from preliminary evidence of a Phase I

Examine B7H3 as a target for an ADC with a duocarmycin payload Presenting a safety overview from Phase 1 Dose Escalation Analyze efficacy from preliminary evidence of a Phase 1 enrollment with focus on prostate cancer

to date have demonstrated a manageable safety profile with evidence of clinical activity by PSA and tumor responses in mCRPC. Enrollment is ongoing in advanced mCRPC, NSCLC, TNBC, SCCHN, and melanoma. Updated data will be provided.

B7-H3 is an important target for immuno-oncology agents for childhood cancers . Our results provide proof-of-principle for the ability of MGC018 to produce profound antitumor activity in select pediatric solid tumor models in a B7-H3 specific manner.

Results to date demonstrate a manageable safety profile, with early evidence of clinical activity in pretreated metastatic melanoma . Cohort expansion is ongoing using a recommended phase 2 dose of 3 mg/kg IV every 3 weeks . The planned enrollment includes advanced metastatic castrate-resistant prostate cancer, melanoma, triple-negative breast cancer, and non-small cell lung cancer.

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.

Importantly, MGC018 exhibited a favorable pharmacokinetic and safety profile in cynomolgus monkeys following repeat-dose administration. The antitumor activity observed preclinically with MGC018, together with the positive safety profile, provides evidence of a potentially favorable therapeutic index and supports the continued development of MGC018 for the treatment of solid cancers.

P1/2, N=150, Recruiting, MacroGenics | Trial primary completion date: Aug 2020 --> Mar 2022

MGC018, a clinical-stage therapeutic comprised of a humanized antibody targeting B7-H3, conjugated to a duocarmycin-based DNA alkylating payload, exhibits a favorable preclinical profile. Results from these syngeneic model studies support the hypothesis that the antitumor activity of the duocarmycin-based MGC018 ADC (1) mediates immunomodulatory activity, (2) is enhanced by combination with checkpoint blockade, and (3) induces immunological memory. Our findings support a clinical strategy that combines MGC018 with checkpoint blockade for the treatment of B7-H3-expressing solid cancers.