Delving into the Latest Updates on PPMX-T003 with Synapse

Overview

Basic Info

Drug Type

Monoclonal antibody

Synonyms

Target

TfR1

Mechanism

TfR1 antagonists(Transferrin receptor protein 1 antagonists)

Therapeutic Areas

NeoplasmsHemic and Lymphatic DiseasesOther Diseases+ [1]

Active Indication

Polycythemia VeraLarge Granular Lymphocytic Leukemia

Inactive Indication-

Originator Organization

Perseus Proteomics, Inc.

Active Organization

Tokai University

Perseus Proteomics, Inc.

Inactive Organization-

Drug Highest PhasePhase 1

First Approval Date-

Regulation-

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Author: Nakamura, Naoya ; Hirao, Atsushi ; Nakagawa, So ; Matsuura, Tadashi ; Onizuka, Makoto ; Carreras, Joaquim ; Hasegawa, Ami ; Ando, Kiyoshi ; Yamauchi, Takuji ; Kameda, Kazuaki ; Watanabe, Natsumi ; Yanagiya, Ryo ; Handa, Hiroshi ; Miyatake, Yuji ; Mashima, Tetsuo ; Ueno, Masaya ; Kanamori, Akane ; Kotani, Ai ; Kamakura, Takeshi ; Maeda, Takahiro ; Ishizawa, Kenichi ; Okabe, Sachiko ; Ishii, Keisuke ; Nakayama, Shunya ; Shimizu, Takanobu

AbstractAggressive natural killer cell leukemia (ANKL) is a rare hematological malignancy with a fulminant clinical course. Our previous study revealed that ANKL cells proliferate predominantly in the liver sinusoids and strongly depend on transferrin supplementation. In addition, we demonstrated that liver-resident ANKL cells are sensitive to PPMX-T003, an anti-human transferrin receptor 1 inhibitory antibody, whereas spleen-resident ANKL cells are resistant to transferrin receptor 1 inhibition. However, the microenvironmental factors that regulate the iron dependency of ANKL cells remain unclear. In this study, we first revealed that the anti-neoplastic effect of PPMX-T003 was characterized by DNA double-strand breaks in a DNA replication-dependent manner, similar to conventional cytotoxic agents. We also found that the influx of extracellular amino acids via LAT1 stimulated sensitivity to PPMX-T003. Taken together, we discovered that the amount of extracellular amino acid influx through LAT1 was the key environmental factor determining the iron dependency of ANKL cells via adjustment of their mTOR/Myc activity, which provides a good explanation for the different sensitivity to PPMX-T003 between liver- and spleen-resident ANKL cells, as the liver sinusoid contains abundant amino acids absorbed from the gut.

27 Jul 2023·Blood

The hepatic niche leads to aggressive natural killer cell leukemia proliferation through the transferrin-transferrin receptor 1 axis.

Article

Author: Ishida, Fumihiro ; Takahashi, Naoto ; Ishihara, Rei ; Nakazawa, Hideyuki ; Carreras, Joaquim ; Harigae, Hideo ; Nakamura, Naoya ; Miyatake, Yuji ; Fukuhara, Noriko ; Iida, Shinsuke ; Yanagiya, Ryo ; Fujioka, Yuki ; Ando, Kiyoshi ; Murakami, Yuki ; Nakagawa, So ; Imadome, Ken-Ichi ; Higuchi, Hiroshi ; Kanda, Yoshinobu ; Matsuura, Tadashi ; Tagawa, Hiroyuki ; Murayama, Hiromichi ; Ishida, Takashi ; Iwabuchi, Sadahiro ; Hashimoto, Shinichi ; Ito, Asahi ; Wada, Hidenori ; Ishizawa, Kenichi ; Kameda, Kazuaki ; Kotani, Ai

Aggressive natural killer cell leukemia (ANKL) is a rare lymphoid neoplasm frequently associated with Epstein-Barr virus, with a disastrously poor prognosis. Owing to the lack of samples from patients with ANKL and relevant murine models, comprehensive investigation of its pathogenesis including the tumor microenvironment (TME) has been hindered. Here we established 3 xenograft mice derived from patients with ANKL (PDXs), which enabled extensive analysis of tumor cells and their TME. ANKL cells primarily engrafted and proliferated in the hepatic sinusoid. Hepatic ANKL cells were characterized by an enriched Myc-pathway and proliferated faster than those in other organs. Interactome analyses and in vivo CRISPR-Cas9 analyses revealed transferrin (Tf)-transferrin receptor 1 (TfR1) axis as a potential molecular interaction between the liver and ANKL. ANKL cells were rather vulnerable to iron deprivation. PPMX-T003, a humanized anti-TfR1 monoclonal antibody, showed remarkable therapeutic efficacy in a preclinical setting using ANKL-PDXs. These findings indicate that the liver, a noncanonical hematopoietic organ in adults, serves as a principal niche for ANKL and the inhibition of the Tf-TfR1 axis is a promising therapeutic strategy for ANKL.

01 Jun 2023·Clinical Pharmacology in Drug Development

Phase 1 Clinical Trial of PPMX‐T003, a Novel Human Monoclonal Antibody Specific for Transferrin Receptor 1, to Evaluate Its Safety, Pharmacokinetics, and Pharmacodynamics

Article

Author: Kirisako, Hiromi ; Komatsu, Norio ; Nomura, Fumiko ; Ohira, Yuta ; Yamamoto, Yukiya ; Yokokawa, Takuya ; Araki, Marito ; Matsuura, Tadashi ; Kumagai, Yuji ; Masubuchi, Nami ; Kyoya, Akiko ; Akiyoshi, Hiroko ; Ogama, Yoichiro

AbstractThis study aimed to evaluate the safety, pharmacokinetics, and pharmacodynamics of PPMX‐T003, a novel human monoclonal antibody for transferrin receptor 1 (TFR1), in healthy individuals. Forty participants were enrolled and randomized to PPMX‐T003 dose groups (n = 6/group) and the placebo group (n = 10). The safety and pharmacokinetics profiles were assessed according to the sequential, ascending single‐dose intravenous infusions of PPMX‐T003 from 0.008 mg/kg to 0.25 mg/kg. Adverse events (AEs) after PPMX‐T003 administration occurred in 16 of 30 participants. Any severe AE and AE incidence were not reported, but they tended to increase depending on the dose. Laboratory tests, vital signs, and standard 12‐lead electrocardiogram showed no clinically relevant changes. Five participants experienced an infusion‐related reaction but recovered on days 5–10. Regarding pharmacokinetics, PPMX‐T003 has a nonlinear elimination pattern. PPMX‐T003 in the 0.25 mg/kg group showed apparent (>50%) decreased serum levels of reticulocytes from day 3 and sustained moderate (<10%) fall of hematocrit and hemoglobin counts from day 7. In conclusion, the antibody‐mediated blockade of TFR1 elicited the expected fall in blood cell levels and showed an acceptable safety profile, supporting the continuing development of PPMX‐T003 as a new candidate for polycythemia vera treatment.

100 Deals associated with PPMX-T003

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Polycythemia Vera	Phase 1	JP	Perseus Proteomics, Inc.	24 Aug 2022
Large Granular Lymphocytic Leukemia	Preclinical	JP	Perseus Proteomics, Inc.	-
Large Granular Lymphocytic Leukemia	Preclinical	JP	Tokai University	-