The targeted delivery of interleukin-12 to the carcinoembryonic antigen increases the intratumoral density of NK and CD8+ T cell in an immunocompetent mouse model of colorectal cancer

Abstract

The recent success achieved by immune checkpoint inhibitors in the field of immuno-oncology has been less evident for the treatment of metastatic colorectal cancer (mCRC) patients. To date, cancer immunotherapy has been efficacious only in few patients bearing high mutational burden (less than 25%) mCRCs. In this Communication, we report the generation of a novel antibody cytokine fusion protein (termed Sm3E-mIL12) targeting the CRC-associated carcinoembryonic antigen (CEA). The antibody moiety bound avidly to CEA when immobilized on solid supports, and selectively stained C51 tumor cells transfected with the antigen (C51-CEA). The cytokine payload retained full activity in vitro, as compared to the parental recombinant interleukin-12 (IL12). Ex vivo microscopic analyses revealed a homogenous distribution of Sm3E-mIL12 in the neoplastic mass upon intravenous administration. In vivo, Sm3E-mIL12 was well tolerated up to 180 µg per mouse. The targeted delivery of IL12 to CEA-expressing C51 carcinomas led to durable complete responses in 60% of the treated mice. The intratumoral density of immune effector cells was markedly increased after the third injection of Sm3E-mIL12, in keeping with the progressive regression of the neoplastic mass. The data suggest that a fully human analogue may be considered for the treatment of patients with mCRC.

Generation and in vivo characterization of a novel high-affinity human antibody targeting carcinoembryonic antigen

“…CEA is an attractive target for the treatment of mCRC, as virtually 100% of patients are strongly positive for the antigen. 20 , 24–26 Although several CEA-targeting products have shown great potential in preclinical models, 15 , 17 , 32 , 53 they were typically immunogenic and induced the development of ADAs in many patients. 33 , 34 , 54 By focusing on the development of fully human antibodies isolated from a synthetic antibody library with short CDR3 loops, our group has previously generated and studied in the clinic antibody-cytokine fusions proteins, which were not immunogenic in patients.…”

“… 13 Certain antibody-based therapeutics may allow immunologically “cold” tumors to become “hot,” boosting the antitumor immune response. 14 For example, a tumor-homing antibody moiety may facilitate the delivery of immunostimulatory cytokines to the neoplastic mass, 15–17 increasing the intratumoral density and activity of T cells and natural killer (NK) cells against malignant cells. 18 , 19 In the context of mCRC, carcinoembryonic antigen (CEA) represents the most validated accessible cell surface antigen for antibody-based pharmacodelivery applications.…”

Interleukin‐2 promotes pegylated interferon alpha for hepatitis B surface antigen loss: A retrospective pragmatic clinical study at the Fourth Affiliated Hospital of Zhejiang University Medical College

“…4 As an important nonspecific immune enhancer, IL-2 can enhance the activity and number of NK cells. [6][7][8] In addition, an appropriately low dose of IL-2 can enhance regulatory T cells (Tregs), and strengthen the control and regulation of proinflammatory NK cells 9 and thus, promote the efficiency of interferon in hepatitis B surface antigen (HBsAg) loss. Injection of IL-2 once a week will not cause serious adverse reactions to the human body, and the common adverse reactions are transient redness, swelling, heat, and pain at the injection site.…”

“…As an important nonspecific immune enhancer, IL‐2 can enhance the activity and number of NK cells 6–8 . In addition, an appropriately low dose of IL‐2 can enhance regulatory T cells (Tregs), and strengthen the control and regulation of proinflammatory NK cells 9 and thus, promote the efficiency of interferon in hepatitis B surface antigen (HBsAg) loss.…”