Obiltoxaximab Overview

Introduction of Obiltoxaximab

Obiltoxaximab (ETI-204, trade name Anthim) is an affinity-enhanced, chimeric IgG1 kappa monoclonal antibody (mAb) developed by Elusys Therapeutics and the US Department of Health and Human Services’ Biomedical Advanced Research and Development Authority (BARDA) for the prevention and treatment of inhalational anthrax due to Bacillus anthracis. Obiltoxaximab binds the protective antigen (PA) component of B. anthracis toxin. It has an approximate molecular weight of 148 kDa. Obiltoxaximab has been designed to neutralize the free protective antigen of B. anthracis, thereby inhibiting the lethal effects of anthrax toxins. In March 2016, intravenous obiltoxaximab was approved in the USA for the treatment (in combination with appropriate antibacterial drugs) and prophylaxis of inhalational anthrax.

Mechanism of Action of Obiltoxaximab

Anthrax protective antigen (PA) is the cell-binding part of the B. anthracis anthrax toxin. The anthrax toxin is composed of the PA, lethal factor (LF) and edema factor (EF). The 83kD form of PA (PA83) binds to the anthrax toxin receptor. A 20kD fragment (PA20) is cleaved off the PA83 and the remaining PA63 assembles into ring-shaped oligomer which becomes a membrane pre-channel. Shortly after germination, B. anthracis will secrete an antiphagocytic poly-d-glutamic acid capsule, and a set of three proteins: EF, LF, and PA. These three proteins are alone nontoxic, but can assemble together in the bloodstream or on host cell surfaces to form the anthrax toxin, which belongs to the broader class of toxins called AB toxins. Both EF and LF of the anthrax toxin correspond to the “A” components, and PA corresponds to the “B” component. PA attaches to host cells, recruiting EF and LF to the cell surface, and forms a pore inside the cell that allows entry of EF and LF into the cytosol. PA also provides protective immunity against anthrax infection in animals.

Obiltoxaximab, a human immunoglobulin G1 (IgG1) mAb, exerts its effect by binding to and neutralizing protective antigen, preventing it from binding to cellular receptors. Thus, protective antigen prevents active edema factor and lethal factor from entering the cytoplasm. This chimeric agent consists of enhanced 14B7 VH and VL genes connected to human v1 and K constants. It was derived from murine mAb 14B7 with mutations resulting in a 50-fold increase in affinity and corresponding neutralizing capability. Additionally, the mAb is deimmunized through VH and VL segment changes, decreasing the risk of immunogenicity.

Mechanism of Action of Obiltoxaximab Fig.1 Mechanism of Action of Obiltoxaximab

Table 1. Clinical Projects of Obiltoxaximab*

NCT ID Status Conditions Lead Sponsor Update Time
NCT03088111 Not yet recruiting Infection, Bacterial; Anthrax Elusys Therapeutics March 23, 2017

Table 2. Approved Drugs of Obiltoxaximab**

INN (trade name) Therapeutic area Dose Strength Route Company Marketing start Market
Anthim Bacillus anthracisinfection Solution 100 mg / mL Intravenous Elusys Therapeutics Inc. October 20, 2016

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References
* The table was excerpted from the following website
https://clinicaltrials.gov/ct2/results?cond=&term=Obiltoxaximab
** Information presented in the table were collected from the following website:
https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=125509


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