Genetic alteration of a bispecific ligand-directed toxin targeting human CD19 and CD22 receptors resulting in improved efficacy against systemic B cell malignancy

Daniel A. Vallera; Hua Chen; Andrew R. Sicheneder; Angela Panoskaltsis-Mortari; Elizabeth P. Taras

doi:10.1016/j.leukres.2009.02.006

Genetic alteration of a bispecific ligand-directed toxin targeting human CD19 and CD22 receptors resulting in improved efficacy against systemic B cell malignancy

Daniel A. Vallera, Hua Chen, Andrew R. Sicheneder, Angela Panoskaltsis-Mortari, Elizabeth P. Taras

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

76 Scopus citations

Abstract

A bispecific ligand-directed toxin (BLT) called DT2219ARL consisting of two scFv ligands recognizing CD19 and CD22 and catalytic DT₃₉₀ was genetically enhanced for superior in vivo anti-leukemia activity. Genetic alterations included reverse orienting VH-VL domains and adding aggregation reducing/stabilizing linkers. In vivo, these improvements resulted in previously unseen long-term tumor-free survivors measured in a bioluminescent xenograft imaging model in which the progression of human Raji Burkitt's lymphoma could be tracked in real time and in a Daudi model as well. Studies showed DT2219ARL was potent (IC₅₀s 0.06-0.2 nM range) and selectively blockable. Imaging studies indicated the highly invasive nature of this B cell malignancy model and showed it likely induced pre-terminal hind limb paralysis because of metastasis to spinal regions prevented by DT2219ARL. DT2219ARL represents a new class of bispecific biological that can be continually improved by genetic mutation.

Original language	English (US)
Pages (from-to)	1233-1242
Number of pages	10
Journal	Leukemia research
Volume	33
Issue number	9
DOIs	https://doi.org/10.1016/j.leukres.2009.02.006
State	Published - Sep 2009

Bibliographical note

Funding Information:
This work was supported in part by the US Public Health Service Grants RO1-CA36725 and RO1-CA082154 awarded by the NCI and the NIAID, DHHS and Children's Cancer Research Fund, the Lion's Children's Cancer Fund, and the William Lawrence and Blanche Hughes Fund.

Keywords

Anti-CD19 sFv
Anti-CD22 sFv
Diphtheria toxin
Immunotoxin
Leukemia
Lymphoma
Scid model

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.leukres.2009.02.006

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title = "Genetic alteration of a bispecific ligand-directed toxin targeting human CD19 and CD22 receptors resulting in improved efficacy against systemic B cell malignancy",

abstract = "A bispecific ligand-directed toxin (BLT) called DT2219ARL consisting of two scFv ligands recognizing CD19 and CD22 and catalytic DT390 was genetically enhanced for superior in vivo anti-leukemia activity. Genetic alterations included reverse orienting VH-VL domains and adding aggregation reducing/stabilizing linkers. In vivo, these improvements resulted in previously unseen long-term tumor-free survivors measured in a bioluminescent xenograft imaging model in which the progression of human Raji Burkitt's lymphoma could be tracked in real time and in a Daudi model as well. Studies showed DT2219ARL was potent (IC50s 0.06-0.2 nM range) and selectively blockable. Imaging studies indicated the highly invasive nature of this B cell malignancy model and showed it likely induced pre-terminal hind limb paralysis because of metastasis to spinal regions prevented by DT2219ARL. DT2219ARL represents a new class of bispecific biological that can be continually improved by genetic mutation.",

keywords = "Anti-CD19 sFv, Anti-CD22 sFv, Diphtheria toxin, Immunotoxin, Leukemia, Lymphoma, Scid model",

author = "Vallera, {Daniel A.} and Hua Chen and Sicheneder, {Andrew R.} and Angela Panoskaltsis-Mortari and Taras, {Elizabeth P.}",

note = "Funding Information: This work was supported in part by the US Public Health Service Grants RO1-CA36725 and RO1-CA082154 awarded by the NCI and the NIAID, DHHS and Children's Cancer Research Fund, the Lion's Children's Cancer Fund, and the William Lawrence and Blanche Hughes Fund.",

year = "2009",

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AU - Chen, Hua

AU - Sicheneder, Andrew R.

AU - Panoskaltsis-Mortari, Angela

AU - Taras, Elizabeth P.

N1 - Funding Information: This work was supported in part by the US Public Health Service Grants RO1-CA36725 and RO1-CA082154 awarded by the NCI and the NIAID, DHHS and Children's Cancer Research Fund, the Lion's Children's Cancer Fund, and the William Lawrence and Blanche Hughes Fund.

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N2 - A bispecific ligand-directed toxin (BLT) called DT2219ARL consisting of two scFv ligands recognizing CD19 and CD22 and catalytic DT390 was genetically enhanced for superior in vivo anti-leukemia activity. Genetic alterations included reverse orienting VH-VL domains and adding aggregation reducing/stabilizing linkers. In vivo, these improvements resulted in previously unseen long-term tumor-free survivors measured in a bioluminescent xenograft imaging model in which the progression of human Raji Burkitt's lymphoma could be tracked in real time and in a Daudi model as well. Studies showed DT2219ARL was potent (IC50s 0.06-0.2 nM range) and selectively blockable. Imaging studies indicated the highly invasive nature of this B cell malignancy model and showed it likely induced pre-terminal hind limb paralysis because of metastasis to spinal regions prevented by DT2219ARL. DT2219ARL represents a new class of bispecific biological that can be continually improved by genetic mutation.

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KW - Anti-CD19 sFv

KW - Anti-CD22 sFv

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KW - Immunotoxin

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KW - Lymphoma

KW - Scid model

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Genetic alteration of a bispecific ligand-directed toxin targeting human CD19 and CD22 receptors resulting in improved efficacy against systemic B cell malignancy

Abstract

Bibliographical note

Keywords

UN SDGs

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