The Broad Anti-AML Activity of the CD33/CD3 BiTE Antibody Construct, AMG 330, Is Impacted by Disease Stage and Risk.
The CD33/CD3-bispecific T-cell engaging (BiTE) antibody construct, AMG 330, potently lyses CD33+ leukemic cells in vitro. Using specimens from 41 patients with acute myeloid leukemia (AML), we studied the factors that might contribute to clinical response or resistance. For this purpose, thawed aliq...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2015-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4549148?pdf=render |
| _version_ | 1819162607197618176 |
|---|---|
| author | Kimberly H Harrington Chelsea J Gudgeon George S Laszlo Kathryn J Newhall Angus M Sinclair Stanley R Frankel Roman Kischel Guang Chen Roland B Walter |
| author_facet | Kimberly H Harrington Chelsea J Gudgeon George S Laszlo Kathryn J Newhall Angus M Sinclair Stanley R Frankel Roman Kischel Guang Chen Roland B Walter |
| author_sort | Kimberly H Harrington |
| collection | DOAJ |
| description | The CD33/CD3-bispecific T-cell engaging (BiTE) antibody construct, AMG 330, potently lyses CD33+ leukemic cells in vitro. Using specimens from 41 patients with acute myeloid leukemia (AML), we studied the factors that might contribute to clinical response or resistance. For this purpose, thawed aliquots of primary AML samples were immunophenotypically characterized and subjected to various doses of AMG 330 in the presence or absence of healthy donor T-cells. After 48 hours, drug-specific cytotoxicity was quantified and correlated with CD33 expression levels, amounts of T-cells present, and other disease characteristics. AMG 330 caused modest cytotoxicity that was correlated with the amount of autologous T-cells (P = 0.0001) but not CD33 expression, as AMG 330 exerted marked cytotoxic effects in several specimens with minimal CD33 expression. With healthy donor T-cells added, AMG 330 cytotoxicity depended on the drug dose and effector:target (E:T) cell ratio. High cytotoxic activity was observed even with minimal CD33 expression, and AMG 330 cytotoxicity and CD33 expression correlated only at high E:T cell ratio and high AMG 330 doses (P<0.003). AMG 330 resulted in significantly higher cytotoxicity in specimens from patients with newly diagnosed AML than those with relapsed/refractory disease despite similar levels of CD33 on myeloblasts. AMG 330 cytotoxicity also appeared greater in specimens from patients with favorable-risk disease as compared to other specimens. Together, our data demonstrate that AMG 330 is highly active in primary AML specimens across the entire disease spectrum, while suggesting the presence of yet undefined, CD33-independent, relative resistance mechanisms in specific patient subsets. |
| first_indexed | 2024-12-22T17:30:55Z |
| format | Article |
| id | doaj.art-7a3bde0d88c344aeb0eba671c0c24cfc |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-22T17:30:55Z |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-7a3bde0d88c344aeb0eba671c0c24cfc2022-12-21T18:18:38ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01108e013594510.1371/journal.pone.0135945The Broad Anti-AML Activity of the CD33/CD3 BiTE Antibody Construct, AMG 330, Is Impacted by Disease Stage and Risk.Kimberly H HarringtonChelsea J GudgeonGeorge S LaszloKathryn J NewhallAngus M SinclairStanley R FrankelRoman KischelGuang ChenRoland B WalterThe CD33/CD3-bispecific T-cell engaging (BiTE) antibody construct, AMG 330, potently lyses CD33+ leukemic cells in vitro. Using specimens from 41 patients with acute myeloid leukemia (AML), we studied the factors that might contribute to clinical response or resistance. For this purpose, thawed aliquots of primary AML samples were immunophenotypically characterized and subjected to various doses of AMG 330 in the presence or absence of healthy donor T-cells. After 48 hours, drug-specific cytotoxicity was quantified and correlated with CD33 expression levels, amounts of T-cells present, and other disease characteristics. AMG 330 caused modest cytotoxicity that was correlated with the amount of autologous T-cells (P = 0.0001) but not CD33 expression, as AMG 330 exerted marked cytotoxic effects in several specimens with minimal CD33 expression. With healthy donor T-cells added, AMG 330 cytotoxicity depended on the drug dose and effector:target (E:T) cell ratio. High cytotoxic activity was observed even with minimal CD33 expression, and AMG 330 cytotoxicity and CD33 expression correlated only at high E:T cell ratio and high AMG 330 doses (P<0.003). AMG 330 resulted in significantly higher cytotoxicity in specimens from patients with newly diagnosed AML than those with relapsed/refractory disease despite similar levels of CD33 on myeloblasts. AMG 330 cytotoxicity also appeared greater in specimens from patients with favorable-risk disease as compared to other specimens. Together, our data demonstrate that AMG 330 is highly active in primary AML specimens across the entire disease spectrum, while suggesting the presence of yet undefined, CD33-independent, relative resistance mechanisms in specific patient subsets.http://europepmc.org/articles/PMC4549148?pdf=render |
| spellingShingle | Kimberly H Harrington Chelsea J Gudgeon George S Laszlo Kathryn J Newhall Angus M Sinclair Stanley R Frankel Roman Kischel Guang Chen Roland B Walter The Broad Anti-AML Activity of the CD33/CD3 BiTE Antibody Construct, AMG 330, Is Impacted by Disease Stage and Risk. PLoS ONE |
| title | The Broad Anti-AML Activity of the CD33/CD3 BiTE Antibody Construct, AMG 330, Is Impacted by Disease Stage and Risk. |
| title_full | The Broad Anti-AML Activity of the CD33/CD3 BiTE Antibody Construct, AMG 330, Is Impacted by Disease Stage and Risk. |
| title_fullStr | The Broad Anti-AML Activity of the CD33/CD3 BiTE Antibody Construct, AMG 330, Is Impacted by Disease Stage and Risk. |
| title_full_unstemmed | The Broad Anti-AML Activity of the CD33/CD3 BiTE Antibody Construct, AMG 330, Is Impacted by Disease Stage and Risk. |
| title_short | The Broad Anti-AML Activity of the CD33/CD3 BiTE Antibody Construct, AMG 330, Is Impacted by Disease Stage and Risk. |
| title_sort | broad anti aml activity of the cd33 cd3 bite antibody construct amg 330 is impacted by disease stage and risk |
| url | http://europepmc.org/articles/PMC4549148?pdf=render |
| work_keys_str_mv | AT kimberlyhharrington thebroadantiamlactivityofthecd33cd3biteantibodyconstructamg330isimpactedbydiseasestageandrisk AT chelseajgudgeon thebroadantiamlactivityofthecd33cd3biteantibodyconstructamg330isimpactedbydiseasestageandrisk AT georgeslaszlo thebroadantiamlactivityofthecd33cd3biteantibodyconstructamg330isimpactedbydiseasestageandrisk AT kathrynjnewhall thebroadantiamlactivityofthecd33cd3biteantibodyconstructamg330isimpactedbydiseasestageandrisk AT angusmsinclair thebroadantiamlactivityofthecd33cd3biteantibodyconstructamg330isimpactedbydiseasestageandrisk AT stanleyrfrankel thebroadantiamlactivityofthecd33cd3biteantibodyconstructamg330isimpactedbydiseasestageandrisk AT romankischel thebroadantiamlactivityofthecd33cd3biteantibodyconstructamg330isimpactedbydiseasestageandrisk AT guangchen thebroadantiamlactivityofthecd33cd3biteantibodyconstructamg330isimpactedbydiseasestageandrisk AT rolandbwalter thebroadantiamlactivityofthecd33cd3biteantibodyconstructamg330isimpactedbydiseasestageandrisk AT kimberlyhharrington broadantiamlactivityofthecd33cd3biteantibodyconstructamg330isimpactedbydiseasestageandrisk AT chelseajgudgeon broadantiamlactivityofthecd33cd3biteantibodyconstructamg330isimpactedbydiseasestageandrisk AT georgeslaszlo broadantiamlactivityofthecd33cd3biteantibodyconstructamg330isimpactedbydiseasestageandrisk AT kathrynjnewhall broadantiamlactivityofthecd33cd3biteantibodyconstructamg330isimpactedbydiseasestageandrisk AT angusmsinclair broadantiamlactivityofthecd33cd3biteantibodyconstructamg330isimpactedbydiseasestageandrisk AT stanleyrfrankel broadantiamlactivityofthecd33cd3biteantibodyconstructamg330isimpactedbydiseasestageandrisk AT romankischel broadantiamlactivityofthecd33cd3biteantibodyconstructamg330isimpactedbydiseasestageandrisk AT guangchen broadantiamlactivityofthecd33cd3biteantibodyconstructamg330isimpactedbydiseasestageandrisk AT rolandbwalter broadantiamlactivityofthecd33cd3biteantibodyconstructamg330isimpactedbydiseasestageandrisk |