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Induction of tumor-specific T cell immunity by anti-DR5 antibody therapy.

Takeda K, Yamaguchi N, Akiba H, Kojima Y, Hayakawa Y, Tanner JE, Sayers TJ, Seki N, Okumura K, Yagita H, Smyth MJ - J. Exp. Med. (2004)

Bottom Line: Here we report that a monoclonal antibody (mAb) against the mouse TRAIL receptor, DR5, exhibited potent antitumor effects against TRAIL-sensitive tumor cells in vivo by recruiting Fc receptor-expressing innate immune cells, with no apparent systemic toxicity.Administration of the agonistic anti-DR5 mAb also significantly inhibited experimental and spontaneous tumor metastases.These results suggested that the antibody-based therapy targeting DR5 is an efficient strategy not only to eliminate TRAIL-sensitive tumor cells, but also to induce tumor-specific T cell memory that affords a long-term protection from tumor recurrence.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bukyou-ku, Tokyo 113-8421, Japan. ktakeda@med.juntendo.ac.jp

ABSTRACT
Because tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) preferentially induces apoptosis in tumor cells and plays a critical role in tumor surveillance, its receptor is an attractive target for antibody-mediated tumor therapy. Here we report that a monoclonal antibody (mAb) against the mouse TRAIL receptor, DR5, exhibited potent antitumor effects against TRAIL-sensitive tumor cells in vivo by recruiting Fc receptor-expressing innate immune cells, with no apparent systemic toxicity. Administration of the agonistic anti-DR5 mAb also significantly inhibited experimental and spontaneous tumor metastases. Notably, the anti-DR5 mAb-mediated tumor rejection by innate immune cells efficiently evoked tumor-specific T cell immunity that could also eradicate TRAIL-resistant variants. These results suggested that the antibody-based therapy targeting DR5 is an efficient strategy not only to eliminate TRAIL-sensitive tumor cells, but also to induce tumor-specific T cell memory that affords a long-term protection from tumor recurrence.

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No apparent toxicity of MD5-1 in vivo. (A) Serum AST and ALT levels 20 h after MD5-1 injection. Data are represented as the mean ± SE of 10 mice. Similar results were obtained in two independent experiments at several time points (not depicted). (B) Histological examination (H/E) of liver (×10) and thymus (×5) from MD5-1–treated mice.
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fig3: No apparent toxicity of MD5-1 in vivo. (A) Serum AST and ALT levels 20 h after MD5-1 injection. Data are represented as the mean ± SE of 10 mice. Similar results were obtained in two independent experiments at several time points (not depicted). (B) Histological examination (H/E) of liver (×10) and thymus (×5) from MD5-1–treated mice.

Mentions: Previous studies have suggested a hepatotoxicity of some forms of TRAIL in vitro and in vivo (16, 33). However, significantly elevated serum AST or ALT levels were not observed in BALB/c mice after repeated MD5-1 administration (Fig. 3 A), nor was there obvious histological evidence of tissue pathology in the liver and thymus (Fig. 3 B) as well as other organs including the kidney, brain, lungs, intestine, and skin. Moreover, the MD5-1–treated mice did not show any sign of systemic toxicity as estimated by body weight, gross appearance, or behavior (unpublished data).


Induction of tumor-specific T cell immunity by anti-DR5 antibody therapy.

Takeda K, Yamaguchi N, Akiba H, Kojima Y, Hayakawa Y, Tanner JE, Sayers TJ, Seki N, Okumura K, Yagita H, Smyth MJ - J. Exp. Med. (2004)

No apparent toxicity of MD5-1 in vivo. (A) Serum AST and ALT levels 20 h after MD5-1 injection. Data are represented as the mean ± SE of 10 mice. Similar results were obtained in two independent experiments at several time points (not depicted). (B) Histological examination (H/E) of liver (×10) and thymus (×5) from MD5-1–treated mice.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2211825&req=5

fig3: No apparent toxicity of MD5-1 in vivo. (A) Serum AST and ALT levels 20 h after MD5-1 injection. Data are represented as the mean ± SE of 10 mice. Similar results were obtained in two independent experiments at several time points (not depicted). (B) Histological examination (H/E) of liver (×10) and thymus (×5) from MD5-1–treated mice.
Mentions: Previous studies have suggested a hepatotoxicity of some forms of TRAIL in vitro and in vivo (16, 33). However, significantly elevated serum AST or ALT levels were not observed in BALB/c mice after repeated MD5-1 administration (Fig. 3 A), nor was there obvious histological evidence of tissue pathology in the liver and thymus (Fig. 3 B) as well as other organs including the kidney, brain, lungs, intestine, and skin. Moreover, the MD5-1–treated mice did not show any sign of systemic toxicity as estimated by body weight, gross appearance, or behavior (unpublished data).

Bottom Line: Here we report that a monoclonal antibody (mAb) against the mouse TRAIL receptor, DR5, exhibited potent antitumor effects against TRAIL-sensitive tumor cells in vivo by recruiting Fc receptor-expressing innate immune cells, with no apparent systemic toxicity.Administration of the agonistic anti-DR5 mAb also significantly inhibited experimental and spontaneous tumor metastases.These results suggested that the antibody-based therapy targeting DR5 is an efficient strategy not only to eliminate TRAIL-sensitive tumor cells, but also to induce tumor-specific T cell memory that affords a long-term protection from tumor recurrence.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Juntendo University School of Medicine, 2-1-1 Hongo, Bukyou-ku, Tokyo 113-8421, Japan. ktakeda@med.juntendo.ac.jp

ABSTRACT
Because tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) preferentially induces apoptosis in tumor cells and plays a critical role in tumor surveillance, its receptor is an attractive target for antibody-mediated tumor therapy. Here we report that a monoclonal antibody (mAb) against the mouse TRAIL receptor, DR5, exhibited potent antitumor effects against TRAIL-sensitive tumor cells in vivo by recruiting Fc receptor-expressing innate immune cells, with no apparent systemic toxicity. Administration of the agonistic anti-DR5 mAb also significantly inhibited experimental and spontaneous tumor metastases. Notably, the anti-DR5 mAb-mediated tumor rejection by innate immune cells efficiently evoked tumor-specific T cell immunity that could also eradicate TRAIL-resistant variants. These results suggested that the antibody-based therapy targeting DR5 is an efficient strategy not only to eliminate TRAIL-sensitive tumor cells, but also to induce tumor-specific T cell memory that affords a long-term protection from tumor recurrence.

Show MeSH
Related in: MedlinePlus