Abstract LB-199: APVO436, a bispecific anti-CD123 x anti-CD3 ADAPTIR™ molecule for redirected T-cell cytotoxicity with limited cytokine release, is well tolerated in repeat dose toxicology studies in cynomolgus macaques

Comeau, Michael R.; Gottschalk, Rebecca; Daugherty, Mollie; Sewell, Toddy; Misher, Lynda; Bannink, Jeannette; Johnson, Starrla; Parr, Lara; Kumer, John; Jablonski, David; DeFrancesco, Melissa; Bienvenue, David; Hoyos, Gabriela H.; McMahan, Catherine J.; Gross, Jane A.

doi:10.1158/1538-7445.sabcs18-lb-199

Cited by 5 publications

(7 citation statements)

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“…APVO436 is a humanized BiAb that binds to both CD123 and CD3 [ 26 ]. It is a homodimeric antibody comprised of two sets of binding domains linked to a human immunoglobulin (Ig) G1 fragment crystallizable (Fc) domain [ 29 ].…”

Section: Methodsmentioning

confidence: 99%

“…The α-chain of the interleukin-3 (IL-3) receptor, also known as the CD123 antigen, is broadly expressed on AML cells [ 22 , 23 , 24 , 25 ]. APVO436 is a recombinant CD3-engaging BiAb designed to redirect CTLs in a major histocompatibility complex (MHC)-independent manner to CD123-expressing AML cells [ 26 , 27 ]. Dissimilar to previously described bispecific antibody fragments, APVO436 with its ADAPTIR format binds bivalently to both CD123 and CD3, yet does not cross-link and activate T-cells without a target present [ 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

“…APVO436 is a recombinant CD3-engaging BiAb designed to redirect CTLs in a major histocompatibility complex (MHC)-independent manner to CD123-expressing AML cells [ 26 , 27 ]. Dissimilar to previously described bispecific antibody fragments, APVO436 with its ADAPTIR format binds bivalently to both CD123 and CD3, yet does not cross-link and activate T-cells without a target present [ 26 , 27 ]. APVO436 also incorporates a modified antibody Fc region that improves serum stability, but does not cross-link T-cells or target cells through Fc gamma receptors such as CD16 or CD64 [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

“…Dissimilar to previously described bispecific antibody fragments, APVO436 with its ADAPTIR format binds bivalently to both CD123 and CD3, yet does not cross-link and activate T-cells without a target present [ 26 , 27 ]. APVO436 also incorporates a modified antibody Fc region that improves serum stability, but does not cross-link T-cells or target cells through Fc gamma receptors such as CD16 or CD64 [ 26 ]. Preclinical data comparing APVO436 with a CD3xCD123 dual-affinity re-targeting (DART) molecule, MGD006, evaluating T-cell activation, proliferation, cytotoxicity and cytokine secretion, showed that APVO436 and MDG006 are both effective at stimulating a tumor-directed immune response by inducing a comparable T-cell activation, proliferation and cytotoxicity [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

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Risk, Characteristics and Biomarkers of Cytokine Release Syndrome in Patients with Relapsed/Refractory AML or MDS Treated with CD3xCD123 Bispecific Antibody APVO436

Uckun

Watts

Mims

et al. 2021

Cancers

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We evaluate the risk, characteristics and biomarkers of treatment-emergent cytokine release syndrome (CRS) in patients with relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who received APVO436 during the dose-escalation phase of a Phase 1B study (ClinicalTrials.gov, identifier: NCT03647800). Of four patients who developed Grade ≥ 3 CRS, two received steroid prophylaxis. The dose level, gender, race, obesity, or baseline hematologic parameters in peripheral blood did not predict the risk of CRS. Patients with a higher leukemia burden as determined by a higher total WBC, higher percentage of blasts in bone marrow, or higher percentage of blasts in peripheral blood (by hematopathology or immunophenotyping) did not have a higher incidence of CRS. There was an age difference between patients who did versus patients who did not develop CRS (72.9 ± 1.6 years (Median 73.5 years) vs. 63.3 ± 2.3 years (Median: 65.0 years), which was borderline significant (p = 0.04). Premedication with steroids did not eliminate the risk of CRS. Cytokine profiling in patients who developed CRS after APVO436 infusion indicates that the predominant cytokine in this inflammatory cytokine response was IL-6. APVO436-associated CRS was generally manageable with tocilizumab with or without dexamethasone. Notably, the development of CRS after APVO436 therapy did not appear to be associated with a response. The prolonged stabilization of disease, partial remissions and complete remissions were achieved in both patients who experienced CRS, as well as patients who did not experience CRS after APVO436 infusions.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Risk, Characteristics and Biomarkers of Cytokine Release Syndrome in Patients with Relapsed/Refractory AML or MDS Treated with CD3xCD123 Bispecific Antibody APVO436

Uckun

Watts

Mims

et al. 2021

Cancers

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“…Its expression is associated with chemotherapy resistance and poor prognosis (16,19,20). Several biotherapeutic agents targeting CD123 have been developed as biotherapeutic agents against AML, including the CD123directed recombinant human IL3 fusion toxin Tagraxofusb (SL-401) and bispecific antibodies targeting CD123 antigen, such as bispecific T-cell engagers, dual affinity retargeting antibodies, bispecific killer cell engagers, and trispecific killer cell engagers (21)(22)(23)(24)(25). APVO436 is a humanized bispecific antibody designed to direct host cytotoxic T-cells (CTLs) to CD123-expressing blast cells from patients with hematologic malignancies (25)(26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

Post-hoc Analysis of Pharmacodynamics and Single-Agent Activity of CD3xCD123 Bispecific Antibody APVO436 in Relapsed/Refractory AML and MDS Resistant to HMA or Venetoclax Plus HMA

et al. 2022

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APVO436 is a recombinant bispecific antibody designed to direct host cytotoxic T-cells to CD123-expressing blast cells in patients with hematologic malignancies. APVO436 showed promising tolerability and single-agent activity in relapsed or refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The primary purpose of this post-hoc analysis was to evaluate the therapeutic and pharmacodynamic effects of APVO436 in 14 R/R AML/MDS patients who had failed treatment with hypomethylating agents (HMA) or venetoclax plus HMA prior to being enrolled in the APVO436 Phase 1 dose-escalation study that was recently completed. Eight of these 14 patients had R/R AML and had failed treatment with HMA (N=2) or venetoclax plus HMA (N=6). The remaining 6 patients had R/R MDS and had also failed treatment with HMA (N=5) or venetoclax plus HMA (N=1). They were treated with APVO436 at submicrogram dose levels >0.08 mcg/kg that were active in preclinical NOD/SCID mouse xenograft models of AML. APVO436 activated patients’ T-cells as evidenced by reduced numbers of circulating CD123+CD34+ and CD33+CD34+ peripheral blasts. Single-agent activity was observed at dose levels ranging from 0.1 mcg/kg to 0.7 mcg/kg in 4 R/R AML patients (50%), including 3 patients with prolonged stable disease (SD) and one patient with complete remission (CR). Likewise, 3 MDS patients had SD (50%) and 3 additional MDS patients (50%) had a marrow CR at dose levels ranging from 0.1 mcg/kg to 0.8 mcg/kg. The median survival for the combined group of 14 R/R AML/MDS patients was 282 days. This early evidence of single-agent activity of APVO436 in R/R AML/MDS patients who failed HMA with or without venetoclax provides proof of concept supporting its in vivo immunomodulatory and anti-leukemic activity and warrants further investigation of its clinical impact potential.

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CD123-targeted therapy in acute myeloid leukemia

Espinoza-Gutarra

Green

Zeidner

et al. 2021

Expert Review of Hematology

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Abstract LB-199: APVO436, a bispecific anti-CD123 x anti-CD3 ADAPTIR™ molecule for redirected T-cell cytotoxicity with limited cytokine release, is well tolerated in repeat dose toxicology studies in cynomolgus macaques

Cited by 5 publications

References 0 publications

Risk, Characteristics and Biomarkers of Cytokine Release Syndrome in Patients with Relapsed/Refractory AML or MDS Treated with CD3xCD123 Bispecific Antibody APVO436

Risk, Characteristics and Biomarkers of Cytokine Release Syndrome in Patients with Relapsed/Refractory AML or MDS Treated with CD3xCD123 Bispecific Antibody APVO436

Post-hoc Analysis of Pharmacodynamics and Single-Agent Activity of CD3xCD123 Bispecific Antibody APVO436 in Relapsed/Refractory AML and MDS Resistant to HMA or Venetoclax Plus HMA

CD123-targeted therapy in acute myeloid leukemia

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