Improving Efficacy and Safety of Agonistic Anti-CD40 Antibody Through Extracellular Matrix Affinity

Abstract

CD40 is an immune costimulatory receptor expressed by antigen-presenting cells. Agonistic anti-CD40 antibodies have demonstrated considerable antitumor effects yet can also elicit serious treatment-related adverse events, such as liver toxicity, including in man. We engineered a variant that binds extracellular matrix through a super-affinity peptide derived from placenta growth factor-2 (PlGF-2) to enhance anti-CD40's effects when administered locally. Peritumoral injection of PlGF-2-anti-CD40 antibody showed prolonged tissue retention at the injection site and substantially decreased systemic exposure, resulting in decreased liver toxicity. In four mouse tumor models, PlGF-2-anti-CD40 antibody demonstrated enhanced antitumor efficacy compared with its unmodified form and correlated with activated dendritic cells, B cells, and T cells in the tumor and in the tumor-draining lymph node. Moreover, in a genetically engineered melanoma model that does not respond to checkpoint inhibitors, PlGF-2-anti-CD40 antibody treatment enhanced T-cell infiltration into the tumors and slowed tumor growth. Together, these results demonstrate the marked therapeutic advantages of engineering matrix-binding domains onto agonistic anti-CD40 antibody as a therapeutic given by tumori-regional injection for cancer immunotherapy. Extracellular matrix-binding peptide conjugation to agonistic anti-CD40 antibody enhances antitumor efficacy and reduces treatment-related adverse events. .

Concepts of extracellular matrix remodelling in tumour progression and metastasis

“…Due to their expression in specific pathologies, these ECM alterations can be used as biomarkers and therapeutic targets, for example, by using nanobody technology, which can selectively detect these alterations in vivo and guide therapeutics to the specific location 246 . Several recent examples of ECMtargeted immunotherapies have shown promising results in preclinical models [247][248][249][250] . However, detailed ECM compositions in various disease contexts are still unclear as are the specific targets of different proteases.…”

Antiangiogenic immunotherapy suppresses desmoplastic and chemoresistant intestinal tumors in mice

“…71, 72 and this study, Supplemental Figure 7B), therefore, we were unable to evaluate whether repeated administration of A2V+aCD40 could suppress tumor growth for more extended time periods. Intratumoral-or ECM-targeted delivery of aCD40 antibodies proved highly effective and devoid of systemic toxicity in s.c. sarcoma and melanoma models (72,73). These studies provide a rationale for testing tumor-targeted aCD40 antibodies and evaluating the long-term benefits of the combined treatment in our CRC models.…”

Concomitant or delayed anti-TNF differentially impact on immune-related adverse events and antitumor efficacy after anti-CD40 therapy

“…5 13 In a preclinical study, an engineered CD40 mAb conjugated with extracellular matrix-binding peptide improved antitumor efficacy by improving local delivery and reducing systemic treatmentrelated adverse events. 48 Alternatively, in preclinical mouse models, local treatment of slow-release agonistic anti-CD40 antibody directly into tumors was shown to induce robust antitumor CD8+ T cell responses without systemic toxicity. 49 In patients with metastatic melanoma, a phase I/II trial is currently assessing the safety of intratumor administration of CD40 agonist mAb APX005M in combination with systemic anti-PD1 (NCT02706353).…”