CP-870893 / Pfizer - LARVOL DELTA

Structure of CD40-antibody complex uncovers a unique mechanism of action for Fc gamma receptors-independent agonism (SITC 2024) - "Mutations designed to strengthen the secondary CD40 interaction dramatically improved the agonistic activity of CP-870,893 and allowed achieving a potency equivalent to CD40L natural ligand in primary human immuno-assays. Conclusions These findings reveal a new paradigm of mechanism of action for agonism and provide new ideas to design agonistic antibodies against TNFR superfamily members."

IO biomarker • Oncology • CD40 • CD40LG • CD8 • CD80 • CD86 • IL12A • TNFA

Toxicity of an Fc engineered anti-CD40 antibody is abrogated by intratumoral injection and results in durable anti-tumor immunity in patients (SITC 2021) - P1 | "Efficient CD40 agonism requires receptor multimerization which we achieved by engineering the human anti-CD40 antibody CP-870,893 with 5 point-mutations in the Fc domain selectively increasing its binding to human FcyRIIB (herein ”2141-V11”)...Conclusions Intratumoral therapy with the Fc-enhanced CD40 agonist 2141-V11 has been demonstrated to be safe, with promising signs of early activity in both injected and distant non-injected lesions (figure 1). Trial Registration NCT04059588"

Clinical • IO biomarker • Breast Cancer • Melanoma • Oncology • Solid Tumor

[VIRTUAL] In vivo studies of immunomodulatory a-CTLA-4 antibody in a humanized mouse model (ITOC 2021) - "Conclusions This enables us to test the efficacy of immunomodulatory agonistic antibodies (such as CP-870,893) and checkpoint control antibodies (such as anti-CTLA-4) in eliminating a melanoma-like tumor. Furthermore, parameters like tumor infiltrating human cells und cytokine/chemokine production can be analysed."

Preclinical • Melanoma • Oncology • Solid Tumor

Systemic inflammation is a determinant of outcomes to CD40 agonist-based therapy in pancreatic cancer patients. (PubMed, JCI Insight) - "To gain insight into immunological mechanisms of response and resistance to chemoimmunotherapy, we analyzed blood samples from patients (n=22) with advanced PDA treated with an anti-CD40 mAb (CP-870,893) in combination with gemcitabine. Patients with systemic inflammation, defined by neutrophil-lymphocyte ratio (NLR) >3.1, had a shorter median OS (5.8 vs 12.3mo; p=0.0105) as compared to patients with NLR <3.1. Taken together, our findings identify systemic inflammation as a potential resistance mechanism to a CD40-based chemoimmunotherapy and suggest biomarkers for future studies."

Clinical • IO biomarker • Journal • Gastrointestinal Cancer • Hepatology • Immune Modulation • Immunology • Inflammation • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • CXCL8 • GAS6 • IL6 • NCAM1

A phase I study of an agonist CD40 monoclonal antibody (CP-870,893) in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma (Clin Cancer Res) - P1, N=22; PMID: 23983255; NCT00711191; Sponsor: Pfizer; "CP-870,893 in combination with gemcitabine was well-tolerated and associated with anti-tumor activity in patients with PDA. Changes in FDG uptake detected on PET/CT imaging provide insight into therapeutic benefit."

P1 data • Oncology • Pancreatic Cancer

Tremelimumab and CP-870,893 in Patients With Metastatic Melanoma (clinicaltrials.gov) - P1; N=25; Completed; Sponsor: Abramson Cancer Center of the University of Pennsylvania; Active, not recruiting ➔ Completed

Trial completion • Cardiovascular • Gastrointestinal Cancer • Genetic Disorders • Hematological Disorders • Hemophilia • Immune Modulation • Immunology • Inflammation • Inflammatory Arthritis • Melanoma • Oncology • Reperfusion Injury • Rheumatoid Arthritis • Rheumatology • Solid Tumor

New emerging targets in cancer immunotherapy: the role of Cluster of Differentiation 40 (CD40/TNFR5). (PubMed, ESMO Open) - "Ongoing studies investigate CD40 activation in combination with chemotherapy, radiation, targeted therapies and immunomodulatory agents. Further studies are awaited to specifically identify patients with the greatest clinical benefit based on predictive biomarkers."

Biomarker • IO Biomarker • Journal • Review

HERA-CD40L, a hexavalent CD40 agonist, induces a significant T cell mediated anti-tumor immune response and shows superior activity in direct comparison to benchmark agonistic antibodies (CIMT 2019) - "...Currently, seven different antibodies and only one CD40L-based hexavalent fusion protein (MEDI5083) are in active clinical trials...We performed extensive comparisons to multiple benchmark antibodies in development (including CP-870,893/Selicrelumab)...In summary, HERA-CD40L is a potent agonist able to shows single agent anti-tumor activity both in vitro and in vivo. The MoA is well defined and the biological activity is distinct from and superior to clinical benchmark “agonistic” antibodies."

IO Biomarker

HERA-CD40L, a hexavalent CD40 agonist, induces a significant T cell mediated anti-tumor immune response and shows superior activity in direct comparison to benchmark agonistic antibodies (CIMT 2019) - "...Currently, seven different antibodies and only one CD40L-based hexavalent fusion protein (MEDI5083) are in active clinical trials...We performed extensive comparisons to multiple benchmark antibodies in development (including CP-870,893/Selicrelumab)...In summary, HERA-CD40L is a potent agonist able to shows single agent anti-tumor activity both in vitro and in vivo. The MoA is well defined and the biological activity is distinct from and superior to clinical benchmark “agonistic” antibodies."

IO Biomarker

HERA-CD40L a hexavalent CD40 agonist induces T cell mediated anti-tumor immune response and shows superior activity in direct comparison to benchmark agonistic antibodies (AACR 2019) - "Comparison of HERA-CD40L to anti-CD40 benchmark antibodies (including CP-870,893) revealed superiority for HERA-CD40L in all assays tested. In addition mHERA-CD40L showed single agent anti-tumor activity in the CD40-negative syngeneic MC38-CEA mouse model, suggesting an involvement of the immune system in controlling tumor growth.In summary HERA-CD40L is a potent agonist able to establish single agent anti-tumor immune responses. Comparison to bivalent benchmark antibodies showed superior biological activity of HERA-CD40L and qualifies this molecule as an ideal candidate for combinatorial cancer treatments."