|
- 现金
- 62111 元
- 精华
- 26
- 帖子
- 30441
- 注册时间
- 2009-10-5
- 最后登录
- 2022-12-28
|
23 | GS-2829 / GS- 6779 HBV THERAPEUTIC
VACCINE GENERATES ROBUST,
POLYFUNCTIONAL, GENOTYPE CROSS-
REACTIVE CD8 T CELL RESPONSES
ACCOMPANIED BY HIGH TITERS OF ANTI- HBsAg
ANTIBODIES
Sarah Schmidt 1
, Stephane Daffis 2 ,
Sarah Ahmadi- Erber 1
, Meron Mengistu3 , Daniela
Deutschmann1
, Tetiana Grigoriev4 , Ruth Chu 5 ,
Mohammad Uddin 6 , Moshkani Safiehkhatoon 6 ,
Michael D Robek 6 , Henning Lauterbach1
, Klaus
Orlinger 1
, Simon P Fletcher7 and Scott Balsitis 3,8 ,
(1)Hookipa Pharma, (2)Virology, Gilead Sciences, Inc.,
(3)Virology, Gilead Sciences, (4)Gilead Sciences,
(5)Gilead Sciences, Inc., (6)Immunology and Microbial
Disease, Albany Medical College, (7)Gilead Sciences,
Inc, Foster City, USA, (8)Biology, Gilead Sciences
Background: Over 250 million people are chron-
ically infected with Hepatitis B Virus (HBV), which is
estimated to cause over 800,000 deaths annually.
Novel immunotherapies to achieve functional cure of
chronic hepatitis B (CHB) are urgently needed and
must be capable of inducing CD8 T cell- mediated
clearance of HBV-positive hepatocytes and gener-
ating anti-hepatitis B surface antigen (HBsAg) anti-
bodies to neutralize residual virus. In pursuit of these
goals, we have developed a novel alternating-vector
therapeutic vaccine based on non-replicating arena-
virus vectors. Methods: Genotype variants of HBV
core, polymerase and HBsAg were selected based on
amino acid conservation and proximity to consensus
sequences, then screened as gene fusions in arenavi-
rus vectors. Mutations and truncations in polymerase
were made to inactivate enzymatic activity and elim-
inate poorly conserved regions. Different antigen
designs were evaluated for magnitude of T cell and
antibody response, genotype cross-reactivity, and
manufacturability. Vectors were made based on both
Pichinde virus (PICV) and lymphocytic choriomeningi-
tis virus (LCMV) and differing vector combinations and
dosing strategies were tested in mice and cynomolgus
macaques. Results: An inactivated polymerase and
a fusion protein of HBV core and sAg were identified
as antigens that induced high magnitude, genotype
cross-reactive T cell responses. An alternating immu-
nization strategy utilizing both PICV vectors (GS-2829)
and LCMV vectors (GS- 6779) substantially improved
the magnitude and consistency of HBV-specific T cell
responses, with PICV vectors driving unexpectedly
large increases in anti- HBsAg antibody titer. Upon
optimization of the dosing schedule in cynomolgus
macaques, high-magnitude polyfunctional CD8 T cell
responses were achieved in every animal with bal-
anced targeting of HBV core, HBsAg, and polymerase,
accompanied by an anti- HBsAg antibody response.
Conclusion: Due to its promising preclinical profile,
GS-2829 / GS- 6779 immunization has the potential to
serve as a backbone component of an HBV cure com-
bination regimen.
Disclosures:
Meron Mengistu – Gilead Sciences: Employment;
Michael D Robek – CaroGen Corporation: Consulting;
CaroGen Corporation: Grant/Research Support;
CaroGen Corporation: Stock options; Gilead Sciences:
Grant/Research Support;
Simon P Fletcher – Gilead Sciences, Inc.: Employment;
Gilead Sciences, Inc.: Stock Shareholder;
Scott Balsitis – Gilead Sciences: Employment;
The following people have nothing to disclose:
Mohammad Uddin, Moshkani Safiehkhatoon
Disclosure information not available at the time of publi-
cation: Sarah Schmidt, Stephane Daffis, Sarah Ahmadi-
Erber, Daniela Deutschmann, Tetiana Grigoriev, Ruth
Chu, Henning Lauterbach, Klaus Orlinger |
|
发表于 2022-11-11 21:36