TY - JOUR
T1 - A novel T-cell engaging Bi-specific antibody targeting the leukemia antigen PR1/HLA-A2
AU - Herrmann, Amanda C.
AU - Im, Jin S.
AU - Pareek, Sumedha
AU - Ruiz-Vasquez, Wilfredo
AU - Lu, Sijie
AU - Sergeeva, Anna
AU - Mehrens, Jennifer
AU - He, Hong
AU - Alatrash, Gheath
AU - Sukhumalchandra, Pariya
AU - St John, Lisa
AU - Clise-Dwyer, Karen
AU - Zha, Dongxing
AU - Molldrem, Jeffrey J.
N1 - Publisher Copyright:
© 2019 Herrmann, Im, Pareek, Ruiz-Vasquez, Lu, Sergeeva, Mehrens, He, Alatrash, Sukhumalchandra, St. John, Clise-Dwyer, Zha and Molldrem.
PY - 2019
Y1 - 2019
N2 - Despite substantial advances in the treatment of acute myeloid leukemia (AML), only 30% of patients survive more than 5 years. Therefore, new therapeutics are much needed. Here, we present a novel therapeutic strategy targeting PR1, an HLA-A2 restricted myeloid leukemia antigen. Previously, we have developed and characterized a novel T-cell receptor-like monoclonal antibody (8F4) that targets PR1/HLA-A2 and eliminates AML xenografts by antibody-dependent cellular cytotoxicity (ADCC). To improve the potency of 8F4, we adopted a strategy to link T-cell cytotoxicity with a bi-specific T-cell-engaging antibody that binds PR1/HLA-A2 on leukemia and CD3 on neighboring T-cells. The 8F4 bi-specific antibody maintained high affinity and specific binding to PR1/HLA-A2 comparable to parent 8F4 antibody, shown by flow cytometry and Bio-Layer Interferometry. In addition, 8F4 bi-specific antibody activated donor T-cells in the presence of HLA-A2+ primary AML blasts and cell lines in a dose dependent manner. Importantly, activated T-cells lysed HLA-A2+ primary AML blasts and cell lines after addition of 8F4 bi-specific antibody. In conclusion, our studies demonstrate the therapeutic potential of a novel bi-specific antibody targeting the PR1/HLA-A2 leukemia-associated antigen, justifying further clinical development of this strategy.
AB - Despite substantial advances in the treatment of acute myeloid leukemia (AML), only 30% of patients survive more than 5 years. Therefore, new therapeutics are much needed. Here, we present a novel therapeutic strategy targeting PR1, an HLA-A2 restricted myeloid leukemia antigen. Previously, we have developed and characterized a novel T-cell receptor-like monoclonal antibody (8F4) that targets PR1/HLA-A2 and eliminates AML xenografts by antibody-dependent cellular cytotoxicity (ADCC). To improve the potency of 8F4, we adopted a strategy to link T-cell cytotoxicity with a bi-specific T-cell-engaging antibody that binds PR1/HLA-A2 on leukemia and CD3 on neighboring T-cells. The 8F4 bi-specific antibody maintained high affinity and specific binding to PR1/HLA-A2 comparable to parent 8F4 antibody, shown by flow cytometry and Bio-Layer Interferometry. In addition, 8F4 bi-specific antibody activated donor T-cells in the presence of HLA-A2+ primary AML blasts and cell lines in a dose dependent manner. Importantly, activated T-cells lysed HLA-A2+ primary AML blasts and cell lines after addition of 8F4 bi-specific antibody. In conclusion, our studies demonstrate the therapeutic potential of a novel bi-specific antibody targeting the PR1/HLA-A2 leukemia-associated antigen, justifying further clinical development of this strategy.
KW - Acute myeloid leukemia
KW - Bi-specific antibody
KW - Cancer immunotherapy
KW - PR1
KW - Re-directed cytotoxicity
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U2 - 10.3389/fimmu.2018.03153
DO - 10.3389/fimmu.2018.03153
M3 - Article
C2 - 30713535
AN - SCOPUS:85061027204
SN - 1664-3224
VL - 10
JO - Frontiers in immunology
JF - Frontiers in immunology
IS - JAN
M1 - 3153
ER -