cifurtilimab (SEA-CD40)

The technology was applied to an effector function enhanced agonist CD40 antibody, SEA-CD40, and experiments demonstrate significant reductions in Fc-induced immune activation in vitro and in mice and nonhuman primates despite showing retained efficacy and improved pharmacokinetics compared to the parent antibody. We foresee that this simple, modular system can be rapidly applied to antibodies that suffer from systemic immune activation due to peripheral FcγR binding immediately upon infusion.

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

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.

SEA-CD40 was tolerable as monotherapy and induced potent dose dependent immune cell activation and trafficking consistent with immune activation. Evidence of monotherapy antitumor activity was observed in patients with solid tumors and lymphoma. Further evaluation of SEA-CD40 is warranted, potentially as a component of a combination regimen.

P1, N=159, Terminated, Seagen Inc. | Trial completion date: Oct 2024 --> Apr 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Jan 2024 --> Mar 2023; Study closed due to portfolio prioritization

P2, N=77, Active, not recruiting, Seagen Inc. | Recruiting --> Active, not recruiting | N=200 --> 77

P1, N=159, Active, not recruiting, Seagen Inc. | Trial primary completion date: Dec 2022 --> Jan 2024

The combination of SEA-CD40 + GnP + pembro has an acceptable safety profile and shows evidence of antitumor activity in pts with PDAC. This regimen may warrant further evaluation. Clinical trial information: NCT02376699.

Five indication-specific cohorts will explore 2 different regimens: cohorts 1–3 will receive SEA-CD40 with pembrolizumab while cohorts 4 and 5 will receive SEA-CD40, pembrolizumab, carboplatin, and pemetrexed. All patients will provide written informed consent. Consent All patients will provide written informed consent.

P1, N=159, Active, not recruiting, Seagen Inc. | Trial completion date: Jun 2024 --> Oct 2024 | Trial primary completion date: Jun 2022 --> Dec 2022

P1, N=159, Active, not recruiting, Seagen Inc. | Trial completion date: Feb 2024 --> Jun 2024 | Trial primary completion date: Feb 2022 --> Jun 2022

We present data from an ongoing Phase 1 study (SGNS40-001) in a PDAC cohort evaluating the combination of SEA-CD40, GnP, and pembrolizumab (pembro). The combination of SEA-CD40 + GnP + pembro demonstrated a tolerable safety profile. Evidence of immune activation was observed, consistent with the proposed mechanism of action. Follow-up for response and survival are ongoing.

P2, N=200, Ongoing, Seagen Inc.

P2, N=200, Recruiting, Seagen Inc. | Not yet recruiting --> Recruiting

P2, N=200, Not yet recruiting, Seagen Inc.

The reduction in tumor growth and ability to reprogram the tumor microenvironment in preclinical models lays the foundation for clinical development of agonistic CD40 antibodies (APX005M, ChiLob7/4, ADC-1013, SEA-CD40, selicrelumab, and CDX-1140) that are currently being evaluated in early phase clinical trials. In this article, we focus on CD40 expression and immunity in cancer, agonistic human CD40 antibodies, and their pre-clinical and clinical development. With the broad pro-inflammatory effects of CD40 and its ligand on dendritic cells and macrophages, and downstream B and T cell activation, agonists of this pathway may enhance the anti-tumor activity of other systemic therapies.

P1, N=159, Active, not recruiting, Seagen Inc. | Recruiting --> Active, not recruiting | N=470 --> 159 | Trial completion date: Feb 2022 --> Feb 2024 | Trial primary completion date: Oct 2021 --> Feb 2022

These findings support continued clinical evaluation of SEA-CD40. The ongoing phase 1 clinical trial is actively enrolling and includes a cohort in pancreatic cancer assessing the combination of SEA-CD40, gemcitabine, nab-paclitaxel, and pembrolizumab.