Chi Lob 7/4 / Cancer Research UK, BioNTech - LARVOL DELTA

Nanomechanical binding mechanism of ligands drives agonistic activity. (PubMed, Nat Commun) - "Despite its minor molecular flexibility, hCD40L performs association, dissociation, and re-association of hCD40 ten times faster when compared to ChiLob 7/4. We uncover a distinct binding mechanism that may explain the enhanced cluster formation potential and agonistic activity of the natural ligand and will inspire the design of novel ligand formats."

Journal • Oncology • CD40LG

Structure-guided disulfide engineering restricts antibody conformation to elicit TNFR agonism. (PubMed, Nat Commun) - "Furthermore, we explore structure-guided design of the anti-hCD40 antibody ChiLob7/4 and show that engineering additional disulfides between opposing F(ab') arms can elicit conformational restriction, concomitant with enhanced agonism. These results support a mode where subtle increases in rigidity can deliver significant improvements in immunostimulatory activity, thus providing a strategy for the rational design of more powerful antibody therapeutics."

IO biomarker • Journal • Oncology

Comparison of receptor occupancy and optimal doses of PD1xCD40 and PDL1xCD40 bispecific antibodies using physiologically based pharmacokinetic modeling (SITC 2024) - "For PD1xCD40 BsAb kinetic parameters, YH008 antibody was used; 1 for PDL1xCD40 BsAb, HBM9027 antibody.2 Results The model was validated using PK data for monospecific antibodies against PD1 (pembrolizumab, nivolumab), PDL1 (avelumab, durvalumab, atezolizumab), and CD40 (selicrelumab, Chi Lob 7/4, BI 655064), and showed good agreement with clinical data. Conclusions The developed PBPK model integrating data on immune cell levels, target expression, and binding parameters of PD1xCD40 and PDL1xCD40 BsAbs predicts PK and receptor occupancy of the antibodies in tumor and plasma. The model shows that higher doses of PDL1xCD40 BsAb are required for maximal engagement of target molecules compared to PD1xCD40 BsAb."

IO biomarker • PK/PD data • Hematological Malignancies • Oncology

Hinge disulfides in human IgG2 CD40 antibodies modulate receptor signaling by regulation of conformation and flexibility. (PubMed, Sci Immunol) - "To address the underlying process and reveal how hinge disulfide orientation affects agonistic activity, we generated a series of cysteine to serine exchange variants in the hinge region of the clinically relevant monoclonal antibody ChiLob7/4, directed against the key immune receptor CD40...Small-angle x-ray scattering and ensemble modeling demonstrated that the least flexible variants adopt the fewest conformations and evoke the highest levels of receptor agonism. This covalent change may be amenable for broad implementation to modulate receptor signaling in an epitope-independent manner in future therapeutics."

Journal • Immune Modulation • Immunology • Infectious Disease • Inflammation • Oncology • CD40

Agonistic CD40 Antibodies in Cancer Treatment. (PubMed, Cancers (Basel)) - "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."

IO biomarker • Journal • Review • Gastrointestinal Cancer • Genito-urinary Cancer • Immune Modulation • Immunology • Inflammation • Melanoma • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Renal Cell Carcinoma • Solid Tumor • CD40 • CD8