Targeting cytomegalovirus-infected cells using T cells armed with anti-CD3 × anti-CMV bispecific antibody.
Human cytomegalovirus (CMV) reactivation and infection can lead to poor outcomes after allogeneic stem cell transplantation. We hypothesized that anti-CD3 activated T cells (ATCs) armed with chemically heteroconjugated anti-CD3 × polyclonal anti-CMV bispecific antibody (CMVBi) will target and eliminate CMV-infected cells. Arming doses of CMVBi as low as 0.01 ng/10(6) ATCs was able to mediate specific cytotoxicity (SC) directed at CMV-infected target cells significant above unarmed ATCs at mutiplicities of infection (MOI) between 0.01 and 1. At effector-to-target ratios (E:T) of 25:1, 12.5:1, 6.25:1, and 3.125:1, armed ATCs significantly enhanced killing of CMV-infected targets compared with unarmed ATCs. At an MOI of 1.0, the mean % SC directed at CMV-infected targets cells for CMVBi-armed ATCs at E:T of 3.12, 6.25, and 12.5 were 79%, 81%, and 82%, respectively; whereas the mean % SC for unarmed ATCs at the same E:T were all <20%. ATCs, Cytogam(®), or CMVBi alone did not lyse uninfected or CMV-infected targets. Co-cultures of CMVBi-armed ATCs with CMV-infected targets induced cytokine and chemokine release from armed ATCs. This nonmajor histocompatibility complex restricted strategy for targeting CMV could be used to prevent or treat CMV infections after allogeneic stem cell transplantation or organ transplantation.
Bone Marrow Transplantation and Immunotherapy Program, Wayne State University and Karmanos Cancer Institute, Detroit, MI, USA. luml@karmanos.org
Lawrence G
LG
Lum
Mayur
M
Ramesh
Archana
A
Thakur
Subhashis
S
Mitra
Abhinav
A
Deol
Joseph P
JP
Uberti
Philip E
PE
Pellett
D018033:Antibodies, Bispecific / Q000737:chemistry / Q000276:immunology*; D000914:Antibodies, Viral / Q000737:chemistry / Q000276:immunology*; D000956:Antigens, Viral / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology*; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D003587:Cytomegalovirus / Q000254:growth & development / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D005347:Fibroblasts / Q000276:immunology / Q000473:pathology / Q000821:virology; D006801:Humans; D008213:Lymphocyte Activation; D061251:Primary Cell Culture; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000821:virology
D018033:Antibodies, Bispecific; D000914:Antibodies, Viral; D000956:Antigens, Viral; D017252:CD3 Complex; D016207:Cytokines