TY - JOUR
T1 - LILRB4-targeting antibody–drug conjugates for the treatment of acute myeloid leukemia
AU - Anami, Yasuaki
AU - Deng, Mi
AU - Gui, Xun
AU - Yamaguchi, Aiko
AU - Yamazaki, Chisato M.
AU - Zhang, Ningyan
AU - Zhang, Cheng Cheng
AU - An, Zhiqiang
AU - Tsuchikama, Kyoji
N1 - Funding Information:
We thank Dr. Georgina T. Salazar for editing the article. This work was supported by the NCI grant (1R01CA248736 to C.C. Zhang), the Department of Defense (the Breast Cancer Research Program, W81XWH-18-1-0004 and W81XWH-19-1-0598 to K. Tsuchikama), the Cancer Prevention and Research Institute of Texas (DP150056 and RP180435 to C.C. Zhang; and RP150551 and RP190561 to Z. An), the Welch Foundation (AU-0042-20030616 to Z. An), the
Funding Information:
Y. Anami reports a patent for PCT/US2018/034363 issued, US-2020-0115326-A1 issued, and EU18804968.8-1109/3630189 issued. M. Deng reports other from Immune-Onc Therapeutics (holds equity in Immune-Onc Therapeutics and was listed as an inventor of several LILRB-related patents licensed to Immune-Onc Therapeutics) outside the submitted work. C.M. Yamazaki reports a patent for PCT/US2018/034363 issued, US-2020-0115326-A1 issued, and EU18804968.8-1109/3630189 issued. N. Zhang reports grants from Cancer Prevention and Research Institute of Texas (coinvestigator of the grants: RP150551 and RP190561) during the conduct of the study and Immune-Onc Therapeutics (co-principal investigator for a sponsored research agreement with Immune-Onc and the company licensed the LILRB4 antibody patent from her university), other from Immune-Onc Therapeutics (owns the company stocks through University of Texas out-licensing the patent to the company) outside the submitted work, as well as has a patent for PCT/US2016/020838 and PCT/ US2017/044171 issued (patent on monoclonal antibodies targeting LILRB family members) and PCT/US2018/034363; US-2020-0115326-A1; EU18804968.8-1109/ 3630189 issued (ADC linker chemistry). C.C. Zhang reports grants from NIH and Cancer Prevention and Research Institute of Texas during the conduct of the study, other from Immune-Onc Therapeutics (sponsored research agreement and member of the scientific advisory board, had several patent applications licensed to Immune-One Therapeutics) outside the submitted work, as well as has a patent for PCT/US2016/020838 and PCT/US2017/044171 pending to Immune-Onc Therapeutics. Z. An reports grants from CPRIT (principal investigator on two CPRIT grants: RP150551 and RP190561), Immune-Onc Therapeutics (serves as a coinvestigator for a sponsored research agreement with Immune-Onc Therapeutics), and Welch Foundation (principal investigator of a Welch Foundation grant: AU-0042-20030616) during the conduct of the study, other from Immune-Onc Therapeutics (serves as a member of the scientific advisory board of Immune-Onc Therapeutics) outside the submitted work, as well as has a patent for yes issued (as a coinventor on two patents PCT/US2016/020838 and PCT/US2017/044171). K. Tsuchikama reports grants from Department of Defense during the conduct of the study, as well as has a patent for PCT/US2018/034363 issued, US-2020-0115326-A1 issued, and EU18804968.8-1109/3630189 issued. No potential conflicts of interest were disclosed by the other authors.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/11/1
Y1 - 2020/11/1
N2 - Acute myeloid leukemia (AML) is the most common and aggressive blood cancer in adults. In particular, significant unmet medical needs exist for effective treatment strategies for acute myelomonocytic leukemia (M4) and acute monocytic leukemia (M5) AML subtypes. Antibody–drug conjugates (ADC) are a promising drug class for AML therapy, as demonstrated by the FDA-approved anti-CD33 ADC, gemtuzumab ozogamicin (Mylotarg). However, CD33 is expressed in normal hematopoietic stem cells, highlighting the critical need to identify AML-specific targets to minimize the risk of potential adverse effects. We have demonstrated that the leukocyte immunoglobulin-like receptor subfamily B4 (LILRB4) is expressed at significantly higher levels on monocytic M4 and M5 AML cells than on normal counterparts. Here, we test whether LILRB4 is a promising ADC target to kill monocytic AML cells while sparing healthy counterparts. To this end, we generated ADCs from a humanized anti-LILRB4 mAb and the antimitotic payload, monomethyl auristatin F. The conjugates constructed were characterized and evaluated for LILRB4-specific cell killing potency, toxicity to progenitor cells, pharmacokinetics, and therapeutic efficacy. Our ADC linker technology platform efficiently generated homogeneous anti-LILRB4 ADCs with defined drug-to-antibody ratios. The homogeneous anti-LILRB4 ADCs demonstrated the capacity for LILRB4-mediated internalization, suitable physicochemical properties, and high cell killing potency against LILRB4-positive AML cells. Importantly, our data indicate that these ADCs spare normal progenitor cells. One of our homogeneous conjugates exerted a remarkable therapeutic effect and no significant toxicity in a xenograft mouse model of disseminated human AML. Our findings highlight the clinical potential of antiLILRB4 ADCs in monocytic AML therapy.
AB - Acute myeloid leukemia (AML) is the most common and aggressive blood cancer in adults. In particular, significant unmet medical needs exist for effective treatment strategies for acute myelomonocytic leukemia (M4) and acute monocytic leukemia (M5) AML subtypes. Antibody–drug conjugates (ADC) are a promising drug class for AML therapy, as demonstrated by the FDA-approved anti-CD33 ADC, gemtuzumab ozogamicin (Mylotarg). However, CD33 is expressed in normal hematopoietic stem cells, highlighting the critical need to identify AML-specific targets to minimize the risk of potential adverse effects. We have demonstrated that the leukocyte immunoglobulin-like receptor subfamily B4 (LILRB4) is expressed at significantly higher levels on monocytic M4 and M5 AML cells than on normal counterparts. Here, we test whether LILRB4 is a promising ADC target to kill monocytic AML cells while sparing healthy counterparts. To this end, we generated ADCs from a humanized anti-LILRB4 mAb and the antimitotic payload, monomethyl auristatin F. The conjugates constructed were characterized and evaluated for LILRB4-specific cell killing potency, toxicity to progenitor cells, pharmacokinetics, and therapeutic efficacy. Our ADC linker technology platform efficiently generated homogeneous anti-LILRB4 ADCs with defined drug-to-antibody ratios. The homogeneous anti-LILRB4 ADCs demonstrated the capacity for LILRB4-mediated internalization, suitable physicochemical properties, and high cell killing potency against LILRB4-positive AML cells. Importantly, our data indicate that these ADCs spare normal progenitor cells. One of our homogeneous conjugates exerted a remarkable therapeutic effect and no significant toxicity in a xenograft mouse model of disseminated human AML. Our findings highlight the clinical potential of antiLILRB4 ADCs in monocytic AML therapy.
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U2 - 10.1158/1535-7163.MCT-20-0407
DO - 10.1158/1535-7163.MCT-20-0407
M3 - Article
C2 - 32879051
AN - SCOPUS:85097226235
SN - 1535-7163
VL - 19
SP - 2330
EP - 2339
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 11
ER -