The ROR1 antibody-drug conjugate huXBR1-402-G5-PNU effectively targets ROR11 leukemia

Eileen Y. Hu; Priscilla Do; Swagata Goswami; Jessica Nunes; Chi Ling Chiang; Sara Elgamal; Ann M. Ventura; Carolyn Cheney; Kevan Zapolnik; Erich Williams; Rajeswaran Mani; Frank Frissora; Xiaokui Mo; Lorenz Waldmeier; Roger R. Beerli; Haiyong Peng; Christoph Rader; Meixiao Long; Ulf Grawunder; John C. Byrd; Natarajan Muthusamy

doi:10.1182/bloodadvances.2020003276

The ROR1 antibody-drug conjugate huXBR1-402-G5-PNU effectively targets ROR11 leukemia

Eileen Y. Hu, Priscilla Do, Swagata Goswami, Jessica Nunes, Chi Ling Chiang, Sara Elgamal, Ann M. Ventura, Carolyn Cheney, Kevan Zapolnik, Erich Williams, Rajeswaran Mani, Frank Frissora, Xiaokui Mo, Lorenz Waldmeier, Roger R. Beerli, Haiyong Peng, Christoph Rader, Meixiao Long, Ulf Grawunder, John C. ByrdNatarajan Muthusamy

Huck Institutes of the Life Sciences

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

Abstract

Antibody-drug conjugates directed against tumor-specific targets have allowed targeted delivery of highly potent chemotherapy to malignant cells while sparing normal cells. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal protein with limited expression on normal adult tissues and is overexpressed on the surface of malignant cells in mantle cell lymphoma, acute lymphocytic leukemia with t(1;19)(q23;p13) translocation, and chronic lymphocytic leukemia. This differential expression makes ROR1 an attractive target for antibody-drug conjugate therapy, especially in malignancies such as mantle cell lymphoma and acute lymphocytic leukemia, in which systemic chemotherapy remains the gold standard. Several preclinical and phase 1 clinical studies have established the safety and effectiveness of anti-ROR1 monoclonal antibody based therapies. Herein we describe a humanized, firstin-class anti-ROR1 antibody-drug conjugate, huXBR1-402-G5-PNU, which links a novel anti-ROR1 antibody (huXBR1-402) to a highly potent anthracycline derivative (PNU). We found that huXBR1-402-G5-PNU is cytotoxic to proliferating ROR11 malignant cells in vitro and suppressed leukemia proliferation and extended survival in multiple models of mice engrafted with human ROR11 leukemia. Lastly, we show that the B-cell lymphoma 2 (BCL2)-dependent cytotoxicity of huXBR1-402-G5-PNU can be leveraged by combined treatment strategies with the BCL2 inhibitor venetoclax. Together, our data present compelling preclinical evidence for the efficacy of huXBR1-402-G5-PNU in treating ROR11 hematologic malignancies.

Original language	English (US)
Pages (from-to)	3152-3162
Number of pages	11
Journal	Blood Advances
Volume	5
Issue number	16
DOIs	https://doi.org/10.1182/bloodadvances.2020003276
State	Published - Aug 24 2021

All Science Journal Classification (ASJC) codes

Hematology

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10.1182/bloodadvances.2020003276

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Hu, E. Y., Do, P., Goswami, S., Nunes, J., Chiang, C. L., Elgamal, S., Ventura, A. M., Cheney, C., Zapolnik, K., Williams, E., Mani, R., Frissora, F., Mo, X., Waldmeier, L., Beerli, R. R., Peng, H., Rader, C., Long, M., Grawunder, U., ... Muthusamy, N. (2021). The ROR1 antibody-drug conjugate huXBR1-402-G5-PNU effectively targets ROR11 leukemia. Blood Advances, 5(16), 3152-3162. https://doi.org/10.1182/bloodadvances.2020003276

@article{16a272b5309e4db19288fc4c842e1b66,

title = "The ROR1 antibody-drug conjugate huXBR1-402-G5-PNU effectively targets ROR11 leukemia",

abstract = "Antibody-drug conjugates directed against tumor-specific targets have allowed targeted delivery of highly potent chemotherapy to malignant cells while sparing normal cells. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal protein with limited expression on normal adult tissues and is overexpressed on the surface of malignant cells in mantle cell lymphoma, acute lymphocytic leukemia with t(1;19)(q23;p13) translocation, and chronic lymphocytic leukemia. This differential expression makes ROR1 an attractive target for antibody-drug conjugate therapy, especially in malignancies such as mantle cell lymphoma and acute lymphocytic leukemia, in which systemic chemotherapy remains the gold standard. Several preclinical and phase 1 clinical studies have established the safety and effectiveness of anti-ROR1 monoclonal antibody based therapies. Herein we describe a humanized, firstin-class anti-ROR1 antibody-drug conjugate, huXBR1-402-G5-PNU, which links a novel anti-ROR1 antibody (huXBR1-402) to a highly potent anthracycline derivative (PNU). We found that huXBR1-402-G5-PNU is cytotoxic to proliferating ROR11 malignant cells in vitro and suppressed leukemia proliferation and extended survival in multiple models of mice engrafted with human ROR11 leukemia. Lastly, we show that the B-cell lymphoma 2 (BCL2)-dependent cytotoxicity of huXBR1-402-G5-PNU can be leveraged by combined treatment strategies with the BCL2 inhibitor venetoclax. Together, our data present compelling preclinical evidence for the efficacy of huXBR1-402-G5-PNU in treating ROR11 hematologic malignancies.",

author = "Hu, {Eileen Y.} and Priscilla Do and Swagata Goswami and Jessica Nunes and Chiang, {Chi Ling} and Sara Elgamal and Ventura, {Ann M.} and Carolyn Cheney and Kevan Zapolnik and Erich Williams and Rajeswaran Mani and Frank Frissora and Xiaokui Mo and Lorenz Waldmeier and Beerli, {Roger R.} and Haiyong Peng and Christoph Rader and Meixiao Long and Ulf Grawunder and Byrd, {John C.} and Natarajan Muthusamy",

year = "2021",

month = aug,

day = "24",

doi = "10.1182/bloodadvances.2020003276",

language = "English (US)",

volume = "5",

pages = "3152--3162",

journal = "Blood Advances",

issn = "2473-9529",

publisher = "American Society of Hematology",

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Hu, EY, Do, P, Goswami, S, Nunes, J, Chiang, CL, Elgamal, S, Ventura, AM, Cheney, C, Zapolnik, K, Williams, E, Mani, R, Frissora, F, Mo, X, Waldmeier, L, Beerli, RR, Peng, H, Rader, C, Long, M, Grawunder, U, Byrd, JC & Muthusamy, N 2021, 'The ROR1 antibody-drug conjugate huXBR1-402-G5-PNU effectively targets ROR11 leukemia', Blood Advances, vol. 5, no. 16, pp. 3152-3162. https://doi.org/10.1182/bloodadvances.2020003276

TY - JOUR

T1 - The ROR1 antibody-drug conjugate huXBR1-402-G5-PNU effectively targets ROR11 leukemia

AU - Hu, Eileen Y.

AU - Do, Priscilla

AU - Goswami, Swagata

AU - Nunes, Jessica

AU - Chiang, Chi Ling

AU - Elgamal, Sara

AU - Ventura, Ann M.

AU - Cheney, Carolyn

AU - Zapolnik, Kevan

AU - Williams, Erich

AU - Mani, Rajeswaran

AU - Frissora, Frank

AU - Mo, Xiaokui

AU - Waldmeier, Lorenz

AU - Beerli, Roger R.

AU - Peng, Haiyong

AU - Rader, Christoph

AU - Long, Meixiao

AU - Grawunder, Ulf

AU - Byrd, John C.

AU - Muthusamy, Natarajan

PY - 2021/8/24

Y1 - 2021/8/24

N2 - Antibody-drug conjugates directed against tumor-specific targets have allowed targeted delivery of highly potent chemotherapy to malignant cells while sparing normal cells. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal protein with limited expression on normal adult tissues and is overexpressed on the surface of malignant cells in mantle cell lymphoma, acute lymphocytic leukemia with t(1;19)(q23;p13) translocation, and chronic lymphocytic leukemia. This differential expression makes ROR1 an attractive target for antibody-drug conjugate therapy, especially in malignancies such as mantle cell lymphoma and acute lymphocytic leukemia, in which systemic chemotherapy remains the gold standard. Several preclinical and phase 1 clinical studies have established the safety and effectiveness of anti-ROR1 monoclonal antibody based therapies. Herein we describe a humanized, firstin-class anti-ROR1 antibody-drug conjugate, huXBR1-402-G5-PNU, which links a novel anti-ROR1 antibody (huXBR1-402) to a highly potent anthracycline derivative (PNU). We found that huXBR1-402-G5-PNU is cytotoxic to proliferating ROR11 malignant cells in vitro and suppressed leukemia proliferation and extended survival in multiple models of mice engrafted with human ROR11 leukemia. Lastly, we show that the B-cell lymphoma 2 (BCL2)-dependent cytotoxicity of huXBR1-402-G5-PNU can be leveraged by combined treatment strategies with the BCL2 inhibitor venetoclax. Together, our data present compelling preclinical evidence for the efficacy of huXBR1-402-G5-PNU in treating ROR11 hematologic malignancies.

AB - Antibody-drug conjugates directed against tumor-specific targets have allowed targeted delivery of highly potent chemotherapy to malignant cells while sparing normal cells. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal protein with limited expression on normal adult tissues and is overexpressed on the surface of malignant cells in mantle cell lymphoma, acute lymphocytic leukemia with t(1;19)(q23;p13) translocation, and chronic lymphocytic leukemia. This differential expression makes ROR1 an attractive target for antibody-drug conjugate therapy, especially in malignancies such as mantle cell lymphoma and acute lymphocytic leukemia, in which systemic chemotherapy remains the gold standard. Several preclinical and phase 1 clinical studies have established the safety and effectiveness of anti-ROR1 monoclonal antibody based therapies. Herein we describe a humanized, firstin-class anti-ROR1 antibody-drug conjugate, huXBR1-402-G5-PNU, which links a novel anti-ROR1 antibody (huXBR1-402) to a highly potent anthracycline derivative (PNU). We found that huXBR1-402-G5-PNU is cytotoxic to proliferating ROR11 malignant cells in vitro and suppressed leukemia proliferation and extended survival in multiple models of mice engrafted with human ROR11 leukemia. Lastly, we show that the B-cell lymphoma 2 (BCL2)-dependent cytotoxicity of huXBR1-402-G5-PNU can be leveraged by combined treatment strategies with the BCL2 inhibitor venetoclax. Together, our data present compelling preclinical evidence for the efficacy of huXBR1-402-G5-PNU in treating ROR11 hematologic malignancies.

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U2 - 10.1182/bloodadvances.2020003276

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JO - Blood Advances

JF - Blood Advances

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ER -

The ROR1 antibody-drug conjugate huXBR1-402-G5-PNU effectively targets ROR11 leukemia

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