Abstract 3920
Background
B-cell maturation antigen (BCMA) is a potential therapeutic target in treatment of patients with MM. BCMA is widely expressed at the surface of myeloma cells and induces proliferative signals. BCMA-directed BCMA antibody conjugated with toxin has recently demonstrated outstanding anti-tumor responses and acceptable tolerability in MM treatment, allowing patients to achieve deeper responses with minimally added toxicity.
Methods
We used ELISA and FACS to verify AP163 can be combined with CD3/BCMA protein on the cell surface. We used the reporter gene method to verify that it induced T cell activation and target cell killing. In vivo, efficacy was studied in NCI-H929 and Raji xenograft models in female NPG mice. NPG mice were injected subcutaneously into the right dorsal flank with NCI-H929/Raji cells and human PBMC. Then the mice were treated with AP163 and tumor volume was measured twice/week. Cynomolgus monkeys were mainly used for toxicity testing. Intravenous administration is consistent with clinical administration. Its main toxicological target is the increase of cytokines and a series of adverse reactions.
Results
we constructed AP163 which binds to BCMA-expressing cell lines. AP163 induced both types of cell crosslinking, followed by T cell activation, cytokine production, proliferation and redirected target cell killing, with EC50 values in the picomolar range. The affinities of AP163 with human and cynomolgus CD3 are comparable. In vitro, AP163 only induced minimal cytokine release in the presence of BCMA target. When administered to mice bearing human MM xenografts and human T cells, AP163 eradicated subcutaneous tumors in two xenograft models tested and significantly delayed tumor growth at doses as low as 0.04mg/kg. AP163 displayed a 9-h half-life in cynomolgus and was well tolerated in non-human primates, even at high doses up to 5 mg/kg.
Conclusions
AP163 clears tumor cells in a BCMA+ and T-cell dependent manner in vitro and in vivo. Our preclinical data suggest that AP163 induces less cytokine secretion than a conventional bispecific in vitro, with reduction of tumor cell in vivo. AP163 is highly efficacious, safe and convenient for the treatment of patients with MM.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
National Engineering Laboratory of High Level Expression In Mammalian Cells.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
1735 - mTOR inhibition in the treatment of resistant breast cancer
Presenter: María Rodriguez
Session: Poster Display session 1
Resources:
Abstract
6068 - Study of Photodynamic therapy in vitro
Presenter: Irene Jiménez Munguía
Session: Poster Display session 1
Resources:
Abstract
3011 - The potential of neratinib plus dasatinib in overcoming and preventing neratinib resistance in HER2-positive breast cancer models
Presenter: Neil Conlon
Session: Poster Display session 1
Resources:
Abstract
2644 - Novel HDACi, MHY446, induces apoptosis via regulation of mitochondria-endoplasmic reticulum interaction in HCT116 human colorectal cancer cells
Presenter: Nam Deuk Kim
Session: Poster Display session 1
Resources:
Abstract
3085 - Dual inhibition of TGF-β and AXL as a novel treatment for colorectal cancer
Presenter: Davide Ciardiello
Session: Poster Display session 1
Resources:
Abstract
1314 - PARP inhibition enhances cisplatin sensitivity in cervical cancer by modulating β-catenin signaling
Presenter: Minakshi Mann
Session: Poster Display session 1
Resources:
Abstract
2417 - Synergistic effect of DSF combined treatment with cisplatin in atypical teratoid/rhabdoid tumors (AT/RT)
Presenter: Seung Ah Choi
Session: Poster Display session 1
Resources:
Abstract
1149 - Reactive oxygen species induced by OSU-A9 inhibit the growth of duodenal cancer and gastric cancer cells through dephosphorylating intranuclear pyruvate kinase muscle isozyme M2
Presenter: Li-Yuan Bai
Session: Poster Display session 1
Resources:
Abstract
1862 - New therapy for intrahepatic cholangiocarcinoma targeted to cancer associated fibroblasts
Presenter: Takahiro Yamanaka
Session: Poster Display session 1
Resources:
Abstract
782 - Macrophage-cancer cell fusion is mediated by Phosphatidylserine-CD36 receptor interaction and induced by ionizing radiation
Presenter: Ivan Shabo
Session: Poster Display session 1
Resources:
Abstract