Targeted α particle immunotherapy for myeloid leukemia

Joseph G. Jurcic, Steven M. Larson, George Sgouros, Michael R. McDevitt, Ronald D. Finn, Chaitanya R. Divgi, Åse M. Ballangrud, Klaus A. Hamacher, Dangshe Ma, John L. Humm, Martin W. Brechbiel, Roger Molinet, David A. Scheinberg

Research output: Contribution to journalArticle

Abstract

Unlike β particle-emitting isotopes, a emitters can selectively kill individual cancer cells with a single atomic decay. HuM195, a humanized anti-CD33 monoclonal antibody, specifically targets myeloid leukemia cells and has activity against minimal disease. When labeled with the β-emitters 131I and 90Y, HuM195 can eliminate large leukemic burdens in patients, but it produces prolonged myelosuppression requiring hematopoietic stem cell transplantation at high doses. To enhance the potency of native HuM195 yet avoid the nonspecific cytotoxicity of β-emitting constructs, the α-emitting isotope 213Bi was conjugated to HuM195. Eighteen patients with relapsed and refractory acute myelogenous leukemia or chronic myelomonocytic leukemia were treated with 10.36 to 37.0 MBq/kg 213Bi-HuM195. No significant extramedullary toxicity was seen. All 17 evaluable patients developed myelosuppression, with a median time to recovery of 22 days. Nearly all the 213Bi-HuM195 rapidly localized to and was retained in areas of leukemic involvement, including the bone marrow, liver, and spleen. Absorbed dose ratios between these sites and the whole body were 1000-fold greater than those seen with β-emitting constructs in this antigen system and patient population. Fourteen (93%) of 15 evaluable patients had reductions in circulating blasts, and 14 (78%) of 18 patients had reductions in the percentage of bone marrow blasts. This study demonstrates the safety, feasibility, and antileukemic effects of 213Bi-HuM195, and it is the first proof-of-concept for systemic targeted a particle immunotherapy in humans.

Original languageEnglish (US)
Pages (from-to)1233-1239
Number of pages7
JournalBlood
Volume100
Issue number4
StatePublished - Aug 15 2002
Externally publishedYes

Fingerprint

Myeloid Leukemia
Isotopes
Immunotherapy
Bone
Cytotoxicity
Stem cells
Liver
Refractory materials
Toxicity
Monoclonal Antibodies
Cells
Antigens
Recovery
Bone Marrow
Leukemia, Myelomonocytic, Chronic
Hematopoietic Stem Cell Transplantation
Myeloid Cells
Acute Myeloid Leukemia
Spleen
Safety

ASJC Scopus subject areas

  • Hematology

Cite this

Jurcic, J. G., Larson, S. M., Sgouros, G., McDevitt, M. R., Finn, R. D., Divgi, C. R., ... Scheinberg, D. A. (2002). Targeted α particle immunotherapy for myeloid leukemia. Blood, 100(4), 1233-1239.

Targeted α particle immunotherapy for myeloid leukemia. / Jurcic, Joseph G.; Larson, Steven M.; Sgouros, George; McDevitt, Michael R.; Finn, Ronald D.; Divgi, Chaitanya R.; Ballangrud, Åse M.; Hamacher, Klaus A.; Ma, Dangshe; Humm, John L.; Brechbiel, Martin W.; Molinet, Roger; Scheinberg, David A.

In: Blood, Vol. 100, No. 4, 15.08.2002, p. 1233-1239.

Research output: Contribution to journalArticle

Jurcic, JG, Larson, SM, Sgouros, G, McDevitt, MR, Finn, RD, Divgi, CR, Ballangrud, ÅM, Hamacher, KA, Ma, D, Humm, JL, Brechbiel, MW, Molinet, R & Scheinberg, DA 2002, 'Targeted α particle immunotherapy for myeloid leukemia', Blood, vol. 100, no. 4, pp. 1233-1239.
Jurcic JG, Larson SM, Sgouros G, McDevitt MR, Finn RD, Divgi CR et al. Targeted α particle immunotherapy for myeloid leukemia. Blood. 2002 Aug 15;100(4):1233-1239.
Jurcic, Joseph G. ; Larson, Steven M. ; Sgouros, George ; McDevitt, Michael R. ; Finn, Ronald D. ; Divgi, Chaitanya R. ; Ballangrud, Åse M. ; Hamacher, Klaus A. ; Ma, Dangshe ; Humm, John L. ; Brechbiel, Martin W. ; Molinet, Roger ; Scheinberg, David A. / Targeted α particle immunotherapy for myeloid leukemia. In: Blood. 2002 ; Vol. 100, No. 4. pp. 1233-1239.
@article{6758d2887e4c417ebcf5846aea27a5b0,
title = "Targeted α particle immunotherapy for myeloid leukemia",
abstract = "Unlike β particle-emitting isotopes, a emitters can selectively kill individual cancer cells with a single atomic decay. HuM195, a humanized anti-CD33 monoclonal antibody, specifically targets myeloid leukemia cells and has activity against minimal disease. When labeled with the β-emitters 131I and 90Y, HuM195 can eliminate large leukemic burdens in patients, but it produces prolonged myelosuppression requiring hematopoietic stem cell transplantation at high doses. To enhance the potency of native HuM195 yet avoid the nonspecific cytotoxicity of β-emitting constructs, the α-emitting isotope 213Bi was conjugated to HuM195. Eighteen patients with relapsed and refractory acute myelogenous leukemia or chronic myelomonocytic leukemia were treated with 10.36 to 37.0 MBq/kg 213Bi-HuM195. No significant extramedullary toxicity was seen. All 17 evaluable patients developed myelosuppression, with a median time to recovery of 22 days. Nearly all the 213Bi-HuM195 rapidly localized to and was retained in areas of leukemic involvement, including the bone marrow, liver, and spleen. Absorbed dose ratios between these sites and the whole body were 1000-fold greater than those seen with β-emitting constructs in this antigen system and patient population. Fourteen (93{\%}) of 15 evaluable patients had reductions in circulating blasts, and 14 (78{\%}) of 18 patients had reductions in the percentage of bone marrow blasts. This study demonstrates the safety, feasibility, and antileukemic effects of 213Bi-HuM195, and it is the first proof-of-concept for systemic targeted a particle immunotherapy in humans.",
author = "Jurcic, {Joseph G.} and Larson, {Steven M.} and George Sgouros and McDevitt, {Michael R.} and Finn, {Ronald D.} and Divgi, {Chaitanya R.} and Ballangrud, {{\AA}se M.} and Hamacher, {Klaus A.} and Dangshe Ma and Humm, {John L.} and Brechbiel, {Martin W.} and Roger Molinet and Scheinberg, {David A.}",
year = "2002",
month = "8",
day = "15",
language = "English (US)",
volume = "100",
pages = "1233--1239",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "4",

}

TY - JOUR

T1 - Targeted α particle immunotherapy for myeloid leukemia

AU - Jurcic, Joseph G.

AU - Larson, Steven M.

AU - Sgouros, George

AU - McDevitt, Michael R.

AU - Finn, Ronald D.

AU - Divgi, Chaitanya R.

AU - Ballangrud, Åse M.

AU - Hamacher, Klaus A.

AU - Ma, Dangshe

AU - Humm, John L.

AU - Brechbiel, Martin W.

AU - Molinet, Roger

AU - Scheinberg, David A.

PY - 2002/8/15

Y1 - 2002/8/15

N2 - Unlike β particle-emitting isotopes, a emitters can selectively kill individual cancer cells with a single atomic decay. HuM195, a humanized anti-CD33 monoclonal antibody, specifically targets myeloid leukemia cells and has activity against minimal disease. When labeled with the β-emitters 131I and 90Y, HuM195 can eliminate large leukemic burdens in patients, but it produces prolonged myelosuppression requiring hematopoietic stem cell transplantation at high doses. To enhance the potency of native HuM195 yet avoid the nonspecific cytotoxicity of β-emitting constructs, the α-emitting isotope 213Bi was conjugated to HuM195. Eighteen patients with relapsed and refractory acute myelogenous leukemia or chronic myelomonocytic leukemia were treated with 10.36 to 37.0 MBq/kg 213Bi-HuM195. No significant extramedullary toxicity was seen. All 17 evaluable patients developed myelosuppression, with a median time to recovery of 22 days. Nearly all the 213Bi-HuM195 rapidly localized to and was retained in areas of leukemic involvement, including the bone marrow, liver, and spleen. Absorbed dose ratios between these sites and the whole body were 1000-fold greater than those seen with β-emitting constructs in this antigen system and patient population. Fourteen (93%) of 15 evaluable patients had reductions in circulating blasts, and 14 (78%) of 18 patients had reductions in the percentage of bone marrow blasts. This study demonstrates the safety, feasibility, and antileukemic effects of 213Bi-HuM195, and it is the first proof-of-concept for systemic targeted a particle immunotherapy in humans.

AB - Unlike β particle-emitting isotopes, a emitters can selectively kill individual cancer cells with a single atomic decay. HuM195, a humanized anti-CD33 monoclonal antibody, specifically targets myeloid leukemia cells and has activity against minimal disease. When labeled with the β-emitters 131I and 90Y, HuM195 can eliminate large leukemic burdens in patients, but it produces prolonged myelosuppression requiring hematopoietic stem cell transplantation at high doses. To enhance the potency of native HuM195 yet avoid the nonspecific cytotoxicity of β-emitting constructs, the α-emitting isotope 213Bi was conjugated to HuM195. Eighteen patients with relapsed and refractory acute myelogenous leukemia or chronic myelomonocytic leukemia were treated with 10.36 to 37.0 MBq/kg 213Bi-HuM195. No significant extramedullary toxicity was seen. All 17 evaluable patients developed myelosuppression, with a median time to recovery of 22 days. Nearly all the 213Bi-HuM195 rapidly localized to and was retained in areas of leukemic involvement, including the bone marrow, liver, and spleen. Absorbed dose ratios between these sites and the whole body were 1000-fold greater than those seen with β-emitting constructs in this antigen system and patient population. Fourteen (93%) of 15 evaluable patients had reductions in circulating blasts, and 14 (78%) of 18 patients had reductions in the percentage of bone marrow blasts. This study demonstrates the safety, feasibility, and antileukemic effects of 213Bi-HuM195, and it is the first proof-of-concept for systemic targeted a particle immunotherapy in humans.

UR - http://www.scopus.com/inward/record.url?scp=0037103293&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037103293&partnerID=8YFLogxK

M3 - Article

C2 - 12149203

AN - SCOPUS:0037103293

VL - 100

SP - 1233

EP - 1239

JO - Blood

JF - Blood

SN - 0006-4971

IS - 4

ER -