FcRL5 as a target of antibody-drug conjugates for the treatment of multiple myeloma.
Fc receptor-like 5 (FcRL5/FcRH5/IRTA2/CD307) is a surface protein expressed selectively on B cells and plasma cells. We found that FcRL5 was expressed at elevated levels on the surface of plasma cells from the bone marrow of patients diagnosed with multiple myeloma. This prevalence in multiple myeloma and narrow pattern of normal expression indicate that FcRL5 could be a target for antibody-based therapies for multiple myeloma, particularly antibody-drug conjugates (ADC), potent cytotoxic drugs linked to antibodies via specialized chemical linkers, where limited expression on normal tissues is a key component to their safety. We found that FcRL5 is internalized upon antibody binding, indicating that ADCs to FcRL5 could be effective. Indeed, we found that FcRL5 ADCs were efficacious in vitro and in vivo but the unconjugated antibody was not. The two most effective consisted of our anti-FcRL5 antibody conjugated through cysteines to monomethylauristatin E (MMAE) by a maleimidocaproyl-valine-citrulline-p-aminobenzyloxycarbonyl (MC-vcPAB) linker (anti-FcRL5-MC-vcPAB-MMAE) or conjugated via lysines to the maytansinoid DM4 through a disulfide linker (anti-FcRL5-SPDB-DM4). These two ADCs were highly effective in vivo in combination with bortezomib or lenalidomide, drugs in use for the treatment of multiple myeloma. These data show that the FcRL5 ADCs described herein show promise as an effective treatment for multiple myeloma.
Genentech Research and Early Development. 1 DNA Way, South San Francisco, CA 94080, USA.
Kristi
K
Elkins
Bing
B
Zheng
Maryann
M
Go
Dionysos
D
Slaga
Changchun
C
Du
Suzie J
SJ
Scales
Shang-Fan
SF
Yu
Jacqueline
J
McBride
Ruth
R
de Tute
Andy
A
Rawstron
Andrew S
AS
Jack
Allen
A
Ebens
Andrew G
AG
Polson
D000818:Animals; D000912:Antibodies, Neoplasm / Q000276:immunology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis / Q000187:drug effects; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000276:immunology*; D011961:Receptors, Fc; D015203:Reproducibility of Results; D016896:Treatment Outcome
D000912:Antibodies, Neoplasm; D000970:Antineoplastic Agents; C432367:FCRL5 protein, human; D018796:Immunoconjugates; D011956:Receptors, Cell Surface; D011961:Receptors, Fc