New biologic effective against major infection in early tests

Date:
April 24, 2023
Source:
NYU Langone Health / NYU Grossman School of Medicine
Summary:
A research team has shown in early tests that a bioengineered
drug candidate can counter infection with Staphylococcus aureus --
a bacterial species widely resistant to antibiotics.


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FULL STORY ========================================================================== Researchers at NYU Grossman School of Medicine and Janssen Biotech,
Inc. have shown in early tests that a bioengineered drug candidate
can counter infection with Staphylococcus aureus -- a bacterial species
widely resistant to antibiotics and a major cause of death in hospitalized patients.

Experiments demonstrated that SM1B74, an antibacterial biologic agent, was superior to a standard antibiotic drug at treating mice infected with S.

aureus, including its treatment-resistant form known as MRSA.

Published online April 24 in Cell Host & Microbe,the new paper
describes the early testing of mAbtyrins, a combination molecule
based on an engineered version of a human monoclonal antibody (mAb),
a protein that clings to and marks S. aureus for uptake and destruction
by immune cells. Attached to the mAb are centyrins, small proteins that
prevent these bacteria from boring holes into the human immune cells in
which they hide. As the invaders multiply, these cells die and burst, eliminating their threat to the bacteria.

Together, the experimental treatment targets ten disease-causing
mechanisms employed by S. aureus, but without killing it, say the study authors. This approach promises to address antibiotic resistance, say
the researchers, where antibiotics kill vulnerable strains first, only
to make more space for others that happen to be less vulnerable until
the drugs no longer work.

"To our knowledge, this is the first report showing that mAbtyrins
can drastically reduce the populations of this pathogen in cell
studies, and in live mice infected with drug-resistant strains so
common in hospitals," said lead study author Victor Torres, PhD,
the C.V. Starr Professor of Microbiology and director of the NYU
Langone Health Antimicrobial-Resistant Pathogen Program."Our goal was
to design a biologic that works against S. aureus inside and outside
of cells, while also taking away the weapons it uses to evade the
immune system." One-third of the human population are carriers of
S. aureus without symptoms, but those with weakened immune systems may
develop life-threatening lung, heart, bone, or bloodstream infections, especially among hospitalized patients.

Inside Out The new study is the culmination of a five-year research
partnership between scientists at NYU Grossman School of Medicine and
Janssen to address the unique nature of S. aureus.

The NYU Langone team together with Janssen researchers, published in 2019
a study that found that centyrins interfere with the action of potent
toxins used by S. aureus to bore into immune cells. They used a molecular biology technique to make changes in a single parental centyrin, instantly creating a trillion slightly different versions of it via automation. Out
of this "library," careful screening revealed a small set of centyrins
that cling more tightly to the toxins blocking their function.

Building on this work, the team fused the centyrins to a mAb originally
taken from a patient recovering fromS. aureusinfection. Already primed
by its encounter with the bacteria, the mAb could label the bacterial
cells such that they are pulled into bacteria-destroying pockets inside
of roving immune cells called phagocytes. That is unless the same toxins
that enable S. aureus to drill into immune cells from the outside let
it drill out of the pockets to invade from the inside.

In a "marvel of bioengineering," part of the team's mAbtyrin serves
as the passport recognized by immune cells, which then engulf the
entire, attached mAbtyrin, along with its centyrins, and fold it into
the pockets along with bacteria. Once inside, the centyrins block the
bacterial toxins there. This, say the authors, sets their effort apart
from antibody combinations that target the toxins only outside of cells.

The team made several additional changes to their mAbtyrin that defeat S.

aureus by, for instance, activating chain reactions that amplify the
immune response, as well by preventing certain bacterial enzymes from
cutting up antibodies and others from gumming up their action.

In terms of experiments, the researchers tracked the growth of S. aureus strains commonly occurring in US communities in the presence of primary
human immune cells (phagocytes). Bacterial populations grew almost
normally in the presence of the parental antibody, slightly less well
in the presence of the team's engineered mAb, and half as fast when the mAbtyrin was used.

In another test, 98% of mice treated with a control mAb (no centyrins) developed bacteria-filled sores on their kidneys when infected with a
deadly strain of S. aureus, while only 38% of mice did so when treated
with the mAbtyrin. Further, when these tissues were removed and colonies
of bacteria in them counted, the mice treated with the mAbtyrin had one
hundred times (two logs) fewer bacterial cells than those treated with
a control mAb.

Finally, the combination of small doses of the antibiotic vancomycin with
the mAbtyrin in mice significantly improved the efficacy of the mAbtyrin, resulting in maximum reduction of bacterial loads in the kidneys and
greater than 70% protection from kidney lesions.

"It is incredibly important," said Torres, "that we find new ways to
boost the action of vancomycin, a last line of defense against MRSA."
Along with Torres, authors from the Department of Microbiology at NYU
Langone were Rita Chan, Ashley DuMont, Keenan Lacey, Aidan O'Malley,
and Anna O'keeffe.

The study authors included 13 scientists from Janssen Research &
Development (for details see the study manuscript).

This work was supported by Janssen Biotech, Inc., one of the Janssen Pharmaceutical Companies of Johnson & Johnson, under the auspices of an exclusive license and research collaboration agreement with NYU. Torres
has recently received royalties and consulting compensation from Janssen
and related entities. These interests are being managed in accordance
with NYU Langone policies and procedures.

* RELATED_TOPICS
o Health_&_Medicine
# Immune_System # Lymphoma # HIV_and_AIDS #
Pharmaceuticals
o Plants_&_Animals
# Bacteria # Microbes_and_More # Mice #
Biotechnology_and_Bioengineering
* RELATED_TERMS
o Antibiotic_resistance o Toxic_shock_syndrome o Drug_discovery
o Encephalitis o Penicillin-like_antibiotics o HIV_test o
Urinary_tract_infection o Pneumonia

========================================================================== Story Source: Materials provided by NYU_Langone_Health_/_NYU_Grossman_School_of_Medicine.

Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Peter T. Buckley, Rita Chan, Jeffrey Fernandez, Jinquan Luo,
Keenan A.

Lacey, Ashley L. DuMont, Aidan O'Malley, Randall J. Brezski,
Songmao Zheng, Thomas Malia, Brian Whitaker, Adam Zwolak, Angela
Payne, Desmond Clark, Martin Sigg, Eilyn R. Lacy, Anna Kornilova,
Debra Kwok, Steve McCarthy, Bingyuan Wu, Brian Morrow, Jennifer
Nemeth-Seay, Ted Petley, Sam Wu, William R. Strohl, Anthony Simon
Lynch, Victor J. Torres.

Multivalent human antibody-centyrin fusion protein to prevent and
treat Staphylococcus aureus infections. Cell Host & Microbe, 2023;
DOI: 10.1016/j.chom.2023.04.004 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/04/230424133548.htm

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