Abstract DDT01-05: First-in-class T cell-redirecting bispecific antibody targeting glypican-3: a highly tumor-selective antigen

Abstract

Immune checkpoint inhibitors such as anti-PD1 antibodies have shown promising clinical responses in several solid tumors, however there remain patients who do not show an adequate response. Recent biomarker studies have revealed that the presence of neoantigens in the tumor can determine the level of response, and thus the next challenge will be how to target tumors with a neoantigen level that is too low to be recognized by endogenous cytotoxic T cells. Hope in this area is offered by a T cell-redirecting antibody (TRAB), which bispecifically engages CD3 and a tumor antigen, even at very low expression levels, to activate the inherent cytolytic potential of T cells against target tumor cells. A TRAB is highly potent because T cells are activated only in the presence of the targeted antigens and are not restricted by the specificity of the T cell receptor. Given this very potent cytotoxicity, the key to successfully achieving strong antitumor efficacy while avoiding on-target off-tumor toxicity is to select a highly tumor-selective antigen. Our fully humanized IgG TRAB recognizes CD3 and a highly tumor-selective antigen, glypican-3 (GPC3), which is a fetal protein expressed in a wide variety of tissues during development but suppressed in most adult tissues. On the other hand, an inct101e in GPC3 expression has been reported in hepatocellular carcinoma, gastric cancer, lung squamous cell carcinoma, and other cancers. In nonclinical in vitro pharmacology studies, the anti-GPC3 TRAB elicited activation and proliferation of T cells and T cell-dependent cellular cytotoxicity against a wide variety of GPC3-expressing tumor cells, and showed long-lasting in vivo efficacy against tumor expressing very low levels of GPC3 at a few thousand molecules per cell. Furthermore, in an immunocompetent mouse model using human CD3 transgenic mice, anti-GPC3 TRAB showed strong antitumor efficacy against poorly immunogenic tumors, whereas both the immune checkpoint inhibitors and a conventional ADCC-inducing antibody recognizing GPC3 did not show significant efficacy. Pharmacokinetics and toxicology studies in nonhuman primates showed a plasma half-life comparable to a standard IgG drug, allowing a QW or Q2W regimen in humans, with toxicity which was manageable and reversible; the main observations of transient cytokine elevation and associated clinical symptoms were markedly reduced by steroid premedication. Our anti-GPC3 TRAB, which is supported by proprietary antibody engineering technology (ART-Ig) that enables large-scale GMP manufacturing, has promise as a new approach in cancer immunotherapy. Citation Format: Takahiro Ishiguro, Yasuko Kinoshita, Yuji Sano, Yumiko Azuma, Toshiaki Tsunenari, Natsuki Ono, Yoko Kayukawa, Mika Kamata-Sakurai, Hirotake Shiraiwa, Akihisa Kaneko, Werner Frings, Shunichiro Komatsu, Junichi Nezu, Mika Endo. First-in-class T cell-redirecting bispecific antibody targeting glypican-3: a highly tumor-selective antigen. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr DDT01-05.

Glypican-3 targeted positron emission tomography detects sub-centimeter tumors in a xenograft model of hepatocellular carcinoma

“…For HCC, several novel molecular targets are being evaluated for early detection, prognostication, and therapy including GPC3, prostate speci c membrane antigen (PSMA), CD146, and CD38 (12)(13)(14)(15)(16)(17)24). GPC3 is currently a target for T cell therapies (25,26), mAb antagonist and vaccine therapy (27,28), and alpha and beta-particle radionuclide therapy (21,29,30). GPC3-targeted immuno-PET may serve as a companion diagnostic to select patients for GPC3-targeted therapies.…”

A bispecific antibody NXT007 exerts a hemostatic activity in hemophilia A monkeys enough to keep a non-hemophiliac state

“…To generate these asymmetric BsAbs, each anti-FIXa and anti-FX antibody was produced separately by Expi293 expression system (ThermoFisher Scientific) then combined for screening. Proprietary electrostatic steering mutations were introduced into the C H 3 region of each heavy chain to promote heterodimerization (19). In producing NXT007, electrically charged mutation pairs were also introduced at each C H 1/C L interface to form the correct pairing of heavy chain and light chain (18).…”

“…However, the use of a common light chain limited our freedom to identify the most potent light chains for the anti-FIXa arm and anti-FX arm. To overcome this limitation, we identified pairs of charge mutations in the C H 1/C L interface (18) and the C H 3/C H 3 interface (19) that could electrostatically facilitate the correct pairing of heavy and light chains, and heavy chain heterodimerization to enable the industrial manufacturing of a non-common light chain BsAb (Fig. 1B).…”

Immunoglobulin Gamma-Like Therapeutic Bispecific Antibody Formats for Tumor Therapy

“…It was approved by FDA in 2017 for use as routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and paediatric patients with hemophilia A (congenital FVIII deficiency) with FVIII inhibitors. Another product, ERY-974, targeting cluster of differentiation protein 3 (CD3) and Glypican 3 (GPC3) for the treatment of solid tumors, is currently undergoing clinical trials in phase I [30].…”