Targeting Attenuated Interferon-α to Myeloma Cells with a CD38 Antibody Induces Potent Tumor Regression with Reduced Off-Target Activity.
Interferon-α (IFNα) has been prescribed to effectively treat multiple myeloma (MM) and other malignancies for decades. Its use has waned in recent years, however, due to significant toxicity and a narrow therapeutic index (TI). We sought to improve IFNα's TI by, first, attaching it to an anti-CD38 antibody, thereby directly targeting it to MM cells, and, second, by introducing an attenuating mutation into the IFNα portion of the fusion protein rendering it relatively inactive on normal, CD38 negative cells. This anti-CD38-IFNα(attenuated) immunocytokine, or CD38-Attenukine™, exhibits 10,000-fold increased specificity for CD38 positive cells in vitro compared to native IFNα and, significantly, is ~6,000-fold less toxic to normal bone marrow cells in vitro than native IFNα. Moreover, the attenuating mutation significantly decreases IFNα biomarker activity in cynomolgus macaques indicating that this approach may yield a better safety profile in humans than native IFNα or a non-attenuated IFNα immunocytokine. In human xenograft MM tumor models, anti-CD38-IFNα(attenuated) exerts potent anti-tumor activity in mice, inducing complete tumor regression in most cases. Furthermore, anti-CD38-IFNα(attenuated) is more efficacious than standard MM treatments (lenalidomide, bortezomib, dexamethasone) and exhibits strong synergy with lenalidomide and with bortezomib in xenograft models. Our findings suggest that tumor-targeted attenuated cytokines such as IFNα can promote robust tumor killing while minimizing systemic toxicity.
Teva Pharmaceuticals, Global Branded Biologics Division, Redwood City, California, United States of America.
Sarah L
SL
Pogue
Teva Pharmaceuticals, Global Branded Biologics Division, Redwood City, California, United States of America.
Tetsuya
T
Taura
Teva Pharmaceuticals, Global Branded Biologics Division, Redwood City, California, United States of America.
Mingying
M
Bi
Teva Pharmaceuticals, Global Branded Biologics Division, Redwood City, California, United States of America.
Yong
Y
Yun
Teva Pharmaceuticals, Global Branded Biologics Division, Redwood City, California, United States of America.
Angela
A
Sho
Teva Pharmaceuticals, Global Branded Biologics Division, Redwood City, California, United States of America.
Glen
G
Mikesell
Teva Pharmaceuticals, Global Branded Biologics Division, Sydney, Australia.
Collette
C
Behrens
Teva Pharmaceuticals, Global Branded Biologics Division, Netanya, Israel.
Maya
M
Sokolovsky
Teva Pharmaceuticals, Global Branded Biologics Division, Netanya, Israel.
Hussein
H
Hallak
Teva Pharmaceuticals, Global Branded Biologics Division, Netanya, Israel.
Moti
M
Rosenstock
The Institute for Myeloma and Bone Cancer Research, West Hollywood, California, United States of America.
Eric
E
Sanchez
The Institute for Myeloma and Bone Cancer Research, West Hollywood, California, United States of America.
Haiming
H
Chen
The Institute for Myeloma and Bone Cancer Research, West Hollywood, California, United States of America.
James
J
Berenson
Teva Pharmaceuticals, Global Branded Biologics Division, Sydney, Australia.
Anthony
A
Doyle
Teva Pharmaceuticals, Global Branded Biologics Division, Redwood City, California, United States of America.
Steffen
S
Nock
Teva Pharmaceuticals, Global Branded Biologics Division, Redwood City, California, United States of America.
David S
DS
Wilson
D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005434:Flow Cytometry; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology* / Q000627:therapeutic use; D008252:Macaca fascicularis; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D016898:Interferon-alpha; D053633:Receptor, Interferon alpha-beta; D051997:ADP-ribosyl Cyclase 1