The novel and potent CD40 agonist KHK2840 augments the antitumor efficacy of anti-PD-1 antibody and paclitaxel

Lack of tumor-reactive cytotoxic T lymphocytes (CTLs) limits the antitumor efficacy of immune checkpoint inhibitors (ICIs). CD40 agonists have been expected to overcome this limitation by generating tumor-reactive CTLs. However, the clinical efficacy of CD40 agonistic antibodies is not as good as in...

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Published inCancer science
Main Authors Kobayashi, Chiaki, Suzuki-Imaizumi, Minami, Sakaguchi, Yasuko, Ishii, Toshihiko, Adachi, Maiko, Kaneda, Ayumi, Ebihara, Ritsuko, Saito, Masato, Uemori, Takeshi, Mori, Kiyotoshi
Format Journal Article
LanguageEnglish
Published England 08.10.2024
Subjects
toxicology
PD‐1 inhibitor
CD40 antigen
monoclonal antibody
immunotherapy
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Summary:Lack of tumor-reactive cytotoxic T lymphocytes (CTLs) limits the antitumor efficacy of immune checkpoint inhibitors (ICIs). CD40 agonists have been expected to overcome this limitation by generating tumor-reactive CTLs. However, the clinical efficacy of CD40 agonistic antibodies is not as good as in non-clinical studies. The novel human CD40 (hCD40) agonist KHK2840 is a fully human anti-CD40 IgG2 agonistic antibody that is Fc-engineered to minimize complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity. Compared to other hCD40 agonists, KHK2840 exhibited the most potent hCD40 agonistic signal in tumor-bearing hCD40 transgenic mice and human peripheral blood B cells. Moreover, KHK2840 enhanced the antitumor efficacy of the antiprogrammed cell death 1 antibody and paclitaxel. Comprehensive immune profiling revealed that the antitumor immune response of the triple combination involved tumor-draining lymph nodes in addition to tumor microenvironments. This suggests that a coordinated antitumor immune response between tumors and lymph nodes may underlie the synergistic antitumor efficacy of the triple combination therapy. Finally, a toxicology study in cynomolgus monkeys demonstrated that KHK2840 activated the CD40 signal with tolerable toxicological properties. These results indicate that KHK2840 is a novel and potent hCD40 agonistic antibody for cancer immunotherapy, which is expected to augment the antitumor efficacy of ICIs and chemotherapy.
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ISSN:1347-9032
1349-7006
1349-7006
DOI:10.1111/cas.16366