A TNF-related apoptosis-inducing ligand (TRAIL) belongs to the TNF superfamily, and is a protein that induces apoptosis in various types of cancer cells. TRAIL forms a trimer in vivo and binds to a TRAIL receptor (e.g., TRAIL-R1 or TRAIL-R2) containing a death domain in its intracellular region. When TRAIL binds to TRAIL receptors, they aggregate with each other to form a trimer, and apoptotic signals are then transmitted intracellularly. Examples of known TRAIL receptors include TRAIL-R3, TRAIL-R4, and a soluble receptor (i.e., osteoprotegerin), in addition to the TRAIL-R1 and TRAIL-R2 described above (FIG. 1). TRAIL-R3, TRAIL-R4, and osteoprotegerin completely or partially lack death domains, and such receptors do not induce apoptosis even if TRAIL binds thereto. Thus, such receptors are referred to as “decoy receptors.”
TRAIL is less likely to cause apoptosis of normal cells. Thus, the development thereof as an antitumor agent has been in progress. In order to efficiently induce cancer cell apoptosis with the use of TRAIL, however, it is necessary to develop a system in which TRAIL efficiently binds to TRAIL-R1 and TRAIL-R2 without binding to the decoy receptors to deliver apoptotic signals to the cells. Agonistic antibodies against TRAIL-R1 and TRAIL-R2 can induce apoptosis more effectively than TRAIL, since they do not bind to the decoy receptors, and administration intervals of such antibodies may be longer, since the blood half-life thereof is longer. Accordingly, such antibodies have been subjected to clinical trials (Non-Patent Document 1). However, since HGS-ETR1 (anti-hTRAIL (human TRAIL)-R1 agonistic antibody) and HGS-ETR2 (anti-hTRAIL-R2 agonistic antibody) are divalent antibodies, these antibodies cannot induce trimer formation of TRAIL receptors, without cross-linking of antibodies by NK cells or macrophages having Fc receptors (FIG. 2a). Thus, remarkable therapeutic effects could not be attained through clinical trials of these antibodies (Non-Patent Document 2).
HGS-TR2J (KMTR2) is known as a potent agonistic antibody that allows hTRAIL-R2 molecules on cancer cell membranes to directly aggregate and deliver apoptotic signals without the aid of NK cells or macrophages (Non-Patent Document 3) (FIG. 2b). It is also known that a trimer, tetramer, or pentamer of the llama-derived single-chain VHH antibody against hTRAIL-R2 would very strongly induce apoptosis of cancer cells expressing hTRAIL-R2 without the aid of NK cells or macrophages (Patent Document 1) (FIG. 3). In contrast, hTRAIL-R1 and hTRAIL-R2 are expressed in various normal human tissues as well as cancer cells. In particular, normal human hepatic cells are sensitive to hTRAIL and the hTRAIL-R agonistic antibody (Non-Patent Document 4 and Non-Patent Document 5). Thus, the hTRAIL-R agonistic antibody is considered to cause hepatic disorders as side effects.
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