Genentech, Inc.

Benny Chih

Peter Hagedorn

Isidro Hotzel

Marianne Lerbech Jensen

Dhaya Seshasayee

Yi-Chun Hsiao

Zhonghua Lin

Amy Easton

Ainhoa Echeverria Larraza

David Verne Hansen

Lukasz Kielpinski

This application discloses, inter alia, certain antibodies that specifically bind to human TREM2 (triggering receptor expressed on myeloid cells 2). In some embodiments, the antibodies act as TREM2 agonists. In some embodiments, antibodies herein specifically bind to the stalk region of intact, human TREM2, without binding to soluble TREM2, which is the product of TREM2 cleavage between residues H157 and S158. In some embodiments, the antibodies act as TREM2 agonists, specifically bind to the stalk region of TREM2 with dissociation constants ranging from 10 nM to as low as 100-500 pM, 10-50 pM, or 1-10 pM, specifically bind to a TREM2 epitope spanning the H157-S158 cleavage site, and do not bind to soluble TREM2. In some embodiments, antibodies herein also inhibit shedding of soluble TREM2 in a human microglia cell model and in vivo in a mouse model, decrease levels of soluble TREM2 in plasma, CSF and/or the brain, enhance survival of human microglia cells, and increase Aβ plaque formation and compaction in a human microglia model (for example, as measured by increased Aβ plaque intensity and/or increased X04 plaque intensity in human microglia), and thus, may provide a number of neuroprotective activities.

Agonists of TREM2

The present invention relates to oligonucleotides that are complementary to and modulate the expression of TMEM106B. The present invention further relates to conjugates of the oligonucleotide and pharmaceutical compositions and methods for treatment of neurological disorders using the oligonucleotide.

Oligonucleotides for modulating TMEM106B expression

Growing community of inventors

South San Francisco, CA, United States of America

Benny Chih