P1, N=18, Not yet recruiting, University of California, San Diego | Initiation date: Feb 2024 --> Jun 2024

P1, N=150, Active, not recruiting, AbbVie | Trial completion date: Nov 2023 --> Sep 2024 | Trial primary completion date: Nov 2023 --> Sep 2024

P1, N=55, Recruiting, Memorial Sloan Kettering Cancer Center | N=25 --> 55 | Trial completion date: Nov 2024 --> Nov 2025 | Trial primary completion date: Nov 2024 --> Nov 2025

P1/2, N=40, Completed, AbbVie | Active, not recruiting --> Completed | Phase classification: P1b/2 --> P1/2

P1/2, N=90, Recruiting, Alligator Bioscience AB | Active, not recruiting --> Recruiting | Phase classification: P1b/2 --> P1/2 | Trial primary completion date: Feb 2024 --> Feb 2025

P1, N=33, Completed, Lyvgen Biopharma Holdings Limited | Terminated --> Completed

P1/2, N=60, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting

P1, N=5, Terminated, HiberCell, Inc. | N=45 --> 5 | Trial completion date: Apr 2027 --> Mar 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Nov 2025 --> Mar 2024; sponsor decision

P1, N=32, Active, not recruiting, Pediatric Brain Tumor Consortium | Trial completion date: Mar 2024 --> Sep 2024

P2, N=99, Recruiting, Memorial Sloan Kettering Cancer Center

P1, N=160, Recruiting, Shattuck Labs, Inc. | N=107 --> 160 | Trial completion date: Oct 2024 --> Dec 2025 | Trial primary completion date: Feb 2024 --> Apr 2025

P1, N=62, Recruiting, Beijing Mabworks Biotech Co., Ltd. | Trial completion date: Jan 2024 --> Dec 2026 | Trial primary completion date: Dec 2023 --> Dec 2025

P1, N=93, Recruiting, Beijng Immunoah Pharma Tech Co., Ltd.

P1/2, N=32, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Apr 2024 --> Apr 2025 | Trial primary completion date: Apr 2024 --> Apr 2025

P2, N=16, Terminated, Washington University School of Medicine | N=24 --> 16 | Trial completion date: Mar 2024 --> Nov 2023 | Recruiting --> Terminated | Trial primary completion date: Mar 2024 --> Nov 2023; Celldex decision

Two independent studies in cynomolgus macaque (Macaca fascicularis) studies were performed to further evaluate, potentially immunotoxicological effects associated with drug-induced adverse events seen in human subjects. Studies conducted in monkeys showed that when selicrelumab is administered at doses currently used in clinical trial patients, via subcutaneous injection, it is safe and effective at stimulating a systemic immune response.

P2, N=77, Active, not recruiting, Seagen Inc. | Trial primary completion date: Oct 2024 --> Jan 2024

P1, N=46, Terminated, Molecular Partners AG | N=78 --> 46 | Recruiting --> Terminated; After completion of the dose-escalation part of the study, the safety profile of MP0317 in monotherapy is considered adequately characterized in the dose-escalation part of the study.

P2, N=26, Not yet recruiting, Cancer Institute and Hospital, Chinese Academy of Medical Sciences

P1, N=80, Completed, Hoffmann-La Roche | Recruiting --> Completed

P2, N=27, Active, not recruiting, Alexander Z. Wei, MD | Recruiting --> Active, not recruiting

P2, N=80, Recruiting, Roswell Park Cancer Institute | Not yet recruiting --> Recruiting

P1, N=30, Recruiting, Annick Desjardins, MD | Trial primary completion date: Dec 2023 --> Dec 2024

P1, N=82, Not yet recruiting, Shandong New Time Pharmaceutical Co., LTD

We emphasize the ongoing development of improved anti-CD40 antibodies and explore strategies for effective combination therapies. Guided by predictive biomarkers, future research should identify patient populations benefiting the most from CD40 activation.

P1, N=18, Not yet recruiting, University of California, San Diego

These findings indicate that a single dose of sotigalimab leads to enhanced antigen presentation that can activate T cells and induce new T cell clones. This restructuring of the TME provides elements which are critical to the development of effective antitumor immune responses and improved clinical outcomes.

P1, N=107, Recruiting, Shattuck Labs, Inc.

P1, N=33, Terminated, Lyvgen Biopharma Holdings Limited | N=93 --> 33 | Trial completion date: Apr 2024 --> Dec 2023 | Recruiting --> Terminated; The study was terminated due to product development strategy adjustment,there were no safety concerns

P2, N=45, Terminated, Apexigen America, Inc. | Completed --> Terminated; Business decision (not due to safety reason).

P2, N=58, Active, not recruiting, University of Texas Southwestern Medical Center | Trial completion date: Nov 2023 --> Sep 2025 | Trial primary completion date: Nov 2023 --> Sep 2025

In this review, we present the current understanding of the mechanism of action for CD40, along with results from the clinical development of agonistic human CD40 antibodies in cancer treatment (selicrelumab, CDX-1140, APX005M, mitazalimab, 2141-V11, SEA-CD40, LVGN7409, and bispecific antibodies). This review also examines the safety profile of CD40 agonists in both preclinical and clinical settings, highlighting optimized dosage levels, potential adverse effects, and strategies to mitigate them.

P1, N=20, Not yet recruiting, University of Pennsylvania

P1/2, N=1287, Recruiting, Genmab | N=647 --> 1287 | Trial primary completion date: Oct 2025 --> Jul 2025

P1, N=102, Enrolling by invitation, Shattuck Labs, Inc. | Recruiting --> Enrolling by invitation | Phase classification: P1b --> P1

P1, N=107, Recruiting, Shattuck Labs, Inc. | Phase classification: P1a/1b --> P1

Higher anti-CSF1R doses are inferior to lower doses in a preclinical model, inducing a suppressive macrophage population, and potentially explaining the disappointing results observed in patients. While it is impossible to directly infer human doses from murine studies, careful intra-species evaluation can provide important insight. Cabiralizumab dose optimization is necessary for this patient population with limited treatment options.

P1, N=10, Completed, Eucure (Beijing) Biopharma Co., Ltd | N=16 --> 10 | Trial completion date: Jul 2023 --> Mar 2023 | Trial primary completion date: Jul 2023 --> Mar 2023

Eligibility includes adult patients with solitary supratentorial rMG (WHO grade 3/4); ≥ 4weeks after chemotherapy, bevacizumab, or investigational agent; adequate organ function; and KPS ≥70%. The RP2D for intratumoral infusion of D2C7-IT+2141-V11 via CED is identified. The protocol was amended to evaluate the addition of cervical perilymphatic injections of 2141-V11 post CED of D2C7-IT+2141-V11.

P1, N=30, Recruiting, Genmab | Not yet recruiting --> Recruiting

This is a single arm phase I pilot study of liposomal doxorubicin, CDX-1140 (CD40 agonist monoclonal antibody), and CDX-301 (recombinant Flt3 ligand) combination therapy in patients with metastatic or unresectable locally advanced metastatic TNBC. Key eligibility criteria are unresectable stage III or stage IV TNBC (ER ≤10%, PR ≤10%, HER2/neu negative), 1st to 3rd line treatment for metastatic disease (1st line patients need to be PD-L1 negative by 22C3 assay), measurable disease by RECIST 1.1 criteria, consent for pre-treatment and on-treatment biopsies of amenable soft tissue tumor lesions, no prior treatment with an anti-CD40 antibody or a Flt3 ligand, no anthracycline treatment in the metastatic setting, no prior progression while on anthracycline-based therapy or within 6 months of completing neoadjuvant chemotherapy, and no history of non-infectious pneumonitis or current pneumonitis. This trial will enroll up to 45 patients across multiple sites (NCT05029999) and is currently open at University of Texas Southwestern Medical Center, Texas Oncology, University of Chicago, University of Texas San Antonio, Sarah Cannon Research Institute, and Johns Hopkins.

Lastly, distinct patient subgroups based on the pattern of transcriptomic alterations could be identified. In summary, the data presented herein reinforce the anticipated mode of action of mitazalimab and support its ongoing clinical development.