eluvixtamab (AMG 330) / Amgen - LARVOL DELTA

STING activation improves T-cell-engaging immunotherapy for acute myeloid leukemia. (PubMed, Blood) - "We established a key role for IFNγ in AMG 330-mediated cytotoxicity against AML cells, and in rendering AML cells responsive to STING agonism. Here, we propose to improve the efficacy of CD33-targeting BsAbs by combining them with a STING agonist."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD33 • IFNG • STING • TNFA

CSF1R Targeting T Cell Engaging Bispecific Antibodies Enable Safe and Efficient Immunotherapies in Acute Myeloid Leukemia (ASH 2024) - "While the use of T cell engaging bispecific antibodies (TCE) targeting B cell lineage antigens such as CD19 (Blinatumomab) or CD20 (Epcoritamab, Glofitamab, Mosuenetuzumab) have induced strong and long-lasting response rates in B cell malignancies (Falchi, Vardhana et al...Early clinical trials of CD33-TCE (JNJ-67571244, AMG330) or CD123-TCE (Vibecotamab) have shown modest clinical activity (response rates ranging between 0 to 16,6%) and a high degree of treatment-emergent adverse events (TEAE) (Ravandi, Bashey et al...In summary, we could show the safety and efficacy of CSF1R-TCB in preclinical in vitro and in vivo models and demonstrate the superior safety profile of CSF1R-TCB compared to CD33-TCB in CB-humanized mouse models. In cell line-derived xenograft models of AML, CSF1R-TCB induced anti-leukemia activity, warranting further preclinical and clinical investigations."

IO biomarker • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • CCL3 • CD123 • CD20 • CD33 • CD34 • CSF1R • CSF2 • IL2 • IL3RA • IL6

Safety and tolerability of AMG 330 in adults with relapsed/refractory AML: a phase 1a dose-escalation study. (PubMed, Leuk Lymphoma) - "CRS was mitigated with stepwise dosing of AMG 330, prophylactic dexamethasone, and early treatment with tocilizumab. Among 60 evaluable patients, eight achieved complete remission or morphologic leukemia-free state; of the 52 non-responders, 37% had ≥50% reduction in AML bone marrow blasts. AMG 330 is a promising CD33-targeted therapeutic strategy for R/R AML."

Journal • P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD33

KEYNOTE-613: Study of AMG 330 in Combination With Pembrolizumab in Adult With Relapsed or Refractory Acute Myeloid Leukemia (clinicaltrials.gov) - P1 | N=1 | Terminated | Sponsor: Amgen | Phase classification: P1b ➔ P1

Combination therapy • Phase classification • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Sting Activation Improves T-Cell Engaging Immunotherapy of Acute Myeloid Leukemia (ASH 2023) - "We propose a novel mechanism by which AMG 330-activated T cells prime and sensitize AML target cells in a forward feedback loop towards STING activation, leading to increased type-I-IFN production and induction of ISGs. The beneficial effect of physiological cGAMP in enhancing AMG 330-mediated cytotoxicity was accompanied by the pronounced expression of effector cytokines and an overall cytotoxic T-cell phenotype. We established a key role for interferon gamma in AMG 330-mediated cytotoxicity of AML cells and in rendering AML cells responsive to STING agonism."

IO biomarker • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Hematological Malignancies • Leukemia • Oncology • Transplantation • CD33 • CXCL10 • CXCL11 • GZMB • IFI16 • IFNA1 • IFNG • IL2 • IRF7 • LAMP1 • RSAD2 • STAT1 • TNFA

Human Plasma Cells Engineered to Produce Bi-Specific T Cell Engagers Show In Vivo Anti-Tumor Efficacy (ASGCT 2023) - "As a next step towards clinical translation in cancer therapy, here we describe the development and testing of a CRISPR Cas9 genome engineering strategy to generate ex vivo genome-engineered human plasma cells that express high levels of either an anti-CD19 (blinatumomab) or anti-CD33 (AMG 330) BiTE. Finally, immunocompromised mice engrafted with anti-CD19-BiTE secreting plasma cells were resistant to expansion of CD19+ patient derived leukemia, a model that mimics the use of the anti-CD19 BiTE blinatumomab as a bridge to hematopoietic stem cell transplant or potential long-term therapy. These findings support further research into genome engineered human plasma cells for use as a local delivery system of BiTEs for the treatment of leukemias, lymphomas, and possibly other cancers."

Preclinical • Bone Marrow Transplantation • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Oncology • Transplantation

CD33 BiTE molecule-mediated immune synapse formation and subsequent T-cell activation is determined by the expression profile of activating and inhibitory checkpoint molecules on AML cells. (PubMed, Cancer Immunol Immunother) - "T-cell fitness was assessed by T-cell function assays in co-cultures and immune synapse formation by applying a CD33 BiTE molecule (AMG 330). The addition of the immunomodulatory drug (IMiD) lenalidomide to co-cultures led to stabilization of immune synapses and improved subsequent T-cell responses. We conclude that target cells modulate CD33 BiTE molecule-dependent T-cell activation and hence, combinatorial strategies might contribute to enhanced efficacy."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Immune Modulation • Leukemia • Oncology • CD33 • CD86

STING activation improves T cell engaging immunotherapy of Acute Myeloid Leukemia (SITC 2022) - "We hypothesized that combining the CD33 BiTE construct AMG 330 with a cGAS-STING agonist has the potential to reverse immunosuppressive mechanisms and augment anti-leukemic activity...This leads to pronounced expression of effector cytokines and an overall cytotoxic T-cell phenotype, contributing to the beneficial effect of cGAMP in enhancing BiTE construct-mediated lysis. Ethics Approval Peripheral blood or bone marrow samples were collected from healthy donors and patients with acute myeloid leukemia at initial diagnosis, relapse, or complete remission after written informed consent was received in accordance with the Declaration of Helsinki and approval was granted by the Institutional Review Board of the Ludwig-Maximilian-Universität (Munich, Germany, reference number: 216-08)."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD33 • GZMB • IL4 • STING • TNFA

A Phase 1 Study of AMG 330 in Subjects With Myeloid Malignancies (clinicaltrials.gov) - P1 | N=96 | Terminated | Sponsor: Amgen | N=256 ➔ 96 | Trial completion date: Aug 2023 ➔ Dec 2021 | Recruiting ➔ Terminated | Trial primary completion date: Aug 2023 ➔ Dec 2021; Amgen prioritization decision

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Acute Myelogenous Leukemia • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

A Phase 1 Study of AMG 330 in Subjects With Myeloid Malignancies (clinicaltrials.gov) - P1 | N=256 | Recruiting | Sponsor: Amgen | Trial completion date: Feb 2023 ➔ Jun 2023 | Trial primary completion date: Feb 2023 ➔ Jun 2023

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

T Cell Engaging Bispecific Antibodies Produce Durable Response in Mesothelin-Positive Patient-Derived Xenograft Models of Pediatric AML (ASH 2021) - "Antibody single-chain variable region (scFv) sequences derived from amatuximab recognizing MSLN and from either blinatumomab or AMG330 targeting CD3 were used to engineer and express two MSLN/CD3-targeting BsAbs: MSLN AMA -CD3 L2K and MSLN AMA -CD3 AMG respectively...Chemotherapy (DA) consisted of 3 doses of 1.5 mg/kg daunorubicin iv and 5 doses of 50 mg/kg cytarabine ip...Conclusion These data validate the efficacy of MSLN-targeting BsAbs in PDX models with endogenous MSLN expression. Because prior MSLN-directed therapies appeared safe in humans, MSLN-targeting BsAbs could be ideal immunotherapies for MSLN-positive pediatric AML patients."

IO biomarker • Preclinical • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • B2M • MSLN

CD33 BiTE® Construct Mediated Immunological Synapse Formation and Downstream Signaling in T Cells Is Dependent on Expression of Costimulatory Molecules on Target Cells (ASH 2021) - "Currently, two CD33xCD3 BiTE ® antibody constructs (AMG 330 & AMG 673) are being investigated in phase I dose escalation trials in patients with relapsed/refractory Acute Myeloid Leukemia (AML) with early evidence of acceptable safety and anti-leukemic activity (Ravandi et al., ASH 2020; Subklewe et al., EHA 2020). They support the notion that T cell co-signaling receptors like CD86 and PD-L1 modulate T-cell response in an early event manner. Prospective analyses in clinical trials are needed to validate the relevance of checkpoint molecule expression on target cells as a potential predictive biomarker for response."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Immune Modulation • Immunology • Inflammation • Leukemia • Oncology • CD33 • CD86 • MAPK4 • PD-L1 • PTPRC • ZAP70

Evolving Exhaustion of T Cells during the Course of the Disease in AML Can be Abrogated By CD33 BiTE® Construct Mediated Cytotoxicity (ASH 2021) - "Additionally, T-cell function was assessed after stimulation with 1) CD3/CD28 beads; 2) AMG 330, a CD33/CD3 specific BiTE ® construct, after incubation with OCI-AML3 target cells; or 3) AMG 330 in an autologous ex vivo long-term culture system after incubation with primary AML cells (pAML)...These observations may highlight the significant role of the AML target cells in shaping a T-cell response. To this end, we will further analyze the longitudinal communication between T cells and their corresponding AML blasts."

IO biomarker • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • CD33 • CD8 • GZMB • HAVCR2 • LAG3 • NR4A1 • PD-1 • TNFA

Immunotherapeutic Targeting of Mesothelin Positive Pediatric AML Using Bispecific T Cell Engaging Antibodies. (PubMed, Cancers (Basel)) - "Using antibody single-chain variable region (scFv) sequences derived from amatuximab-recognizing MSLN, and from either blinatumomab or AMG330 targeting CD3, we engineered and expressed two MSLN/CD3-targeting BsAbs: MSLN-CD3 and MSLN-CD3, respectively. These data validate the in vivo efficacy and specificity of MSLN-targeting BsAbs. Because prior MSLN-directed therapies appeared safe in humans, MSLN-targeting BsAbs could be ideal immunotherapies for MSLN-positive pediatric AML patients."

Clinical • IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • Pediatrics • Transplantation • MSLN

A Phase 1 Study of AMG 330 in Subjects With Myeloid Malignancies (clinicaltrials.gov) - P1; N=256; Recruiting; Sponsor: Amgen; Trial completion date: Aug 2022 ➔ Feb 2023; Trial primary completion date: Aug 2022 ➔ Feb 2023

Clinical • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

A Phase 1 First-in-Human Study of AMG 330, an Anti-CD33 Bispecific T-Cell Engager (BiTE®) Antibody Construct, in Relapsed/Refractory Acute Myeloid Leukemia (R/R AML) (ASH 2018) - "Expected CRS was mitigated through step-up dosing, corticosteroid pretreatment, IV fluids, tocilizumab, and drug interruption if needed; most patients had short periods of CRS which responded well to treatment. Of note, both CR patients had a complete recovery of blood counts after one cycle of treatment. These promising data validate the use of the BiTE® platform to target CD33."

P1 data • Acute Lymphocytic Leukemia • Acute Myelogenous Leukemia • Biosimilar • Cardiovascular • Hematological Disorders • Hematological Malignancies • Leukemia • Neutropenia • Oncology

[VIRTUAL] Updated results from phase I dose-escalation study of AMG 330, a bispecific T-cell engager molecule, in patients with relapsed/refractory acute myeloid leukemia (R/R AML). (ASCO 2020) - P1 | "AMG 330 dosed up to 720 μg/day provided early evidence of acceptable safety profile, drug tolerability and anti-leukemic activity, and supports further dose escalation. Research Funding: Amgen Inc."

Clinical • P1 data • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • CD8

[VIRTUAL] CHARACTERIZATION OF CLINICAL PHARMACOKINETICS AND EXPOSURE-RESPONSE RELATIONSHIPS OF AMG 330, A BISPECIFIC CD33 T-CELL ENGAGER ANTIBODY CONSTRUCT, IN PATIENTS WITH RELAPSED/REFRACTORY AML (EHA 2020) - P1 | "Based on the model, at a baseline leukemic burden of 20%, a 240 µg/day target dose is predicted to result in a 28% and 4% probabilities of developing CRS of grade ≥ 2 and ≥ 3, respectively. Conclusion Clinical pharmacokinetic profile and E-R relationships of AMG 330 were characterized to identify optimal AMG 330 step dosing regimens that minimize the risk for CRS in ongoing and planned clinical investigations."

Clinical • PK/PD data • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology

[VIRTUAL] Characterization of clinical pharmacokinetics and exposure-response relationships of AMG 330, a bispecific CD33 T-cell engager antibody construct, in patients with relapsed/refractory AML. (ASCO 2020) - P1 | "Clinical pharmacokinetic profile and E-R relationships of AMG 330 were characterized to identify optimal AMG 330 dosing regimens that minimize the risk for CRS in ongoing and planned clinical investigations. Research Funding: Amgen Inc."

Clinical • PK/PD data • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology

[VIRTUAL] UPDATE ON PRELIMINARY RESULTS FROM PHASE 1 FIRST-IN-HUMAN DOSE ESCALATION STUDY OF AMG 330 IN PATIENTS WITH RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA (R/R AML) (EHA 2020) - "Preliminary response assessment showed a correlation with lower tumor burden at baseline and with a trend towards higher CD8+ lymphocyte count and E:T ratio at baseline. Conclusion AMG 330 dosed up to 720 μg/day provided early evidence of acceptable safety profile, drug tolerability and anti-leukemic activity, and supports further dose escalation."

Clinical • IO biomarker • P1 data • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • CD8 • PD-1 • PD-L1

Another one BiTEs the dust as Amgen pauses enrollment for phase 1 bispecific trial (FierceBiotech) - "Amgen disclosed the resumption of enrollment in the study of BCMA BiTE pavurutamab during the second-quarter update. Enrollment for the multiple myeloma clinical trial was paused while the company discussed 'protocol modifications to optimize safety monitoring and mitigation with the FDA.'....Amgen is yet to restart enrollment in the paused CD33 and EGFR studies. The CD33 study is paused pending the generation of 'further information on the CD33 program through progression of AMG 330.' Amgen stopped the EGFR study as it prioritized its portfolio."

Enrollment open • Trial termination • Hematological Malignancies • Multiple Myeloma • Oncology

[VIRTUAL] Characterization of clinical pharmacokinetics and exposure-response [E-R] relationships of AMG 330 in R/R AML patients (JSMO 2021) - No abstract available

Clinical • PK/PD data • Acute Myelogenous Leukemia • Oncology

[VIRTUAL] Update on preliminary results from phase 1 First-in-Human dose escalation study of AMG 330 in patients with Relapsed/Refractory Acute Myeloid Leukemia [R/R AML] (JSMO 2021) - No abstract available

Clinical • P1 data • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

A Phase 1 Study of AMG 330 in Subjects With Myeloid Malignancies (clinicaltrials.gov) - P1; N=256; Recruiting; Sponsor: Amgen; Trial completion date: Feb 2025 ➔ Aug 2022; Trial primary completion date: May 2023 ➔ Aug 2022

Clinical • Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Myelodysplastic Syndrome • Oncology

Amgen Reports First Quarter 2021 Financial Results (PRNewswire) - "The following programs continue to enroll patients in dose escalation studies: (i) BiTE® molecules AMG 330 and AMG 427, targeting CD33 and fms-like tyrosine kinase 3 (FLT3), respectively, for acute myeloid leukemia; (ii) AMG 176, a small molecule inhibitor of myeloid cell leukemia 1 (MCL-1) for hematologic malignancies; (iii) HLE BiTE molecules AMG 199 and AMG 910, targeting mucin 17 (MUC17) and claudin 18.2 (CLDN18.2), respectively, for gastric and gastroesophageal junction cancer; (iv) AMG 509, a bivalent T-cell engager XmAb® 2+1 antibody targeting six transmembrane epithelial antigen of the prostate 1 (STEAP1) for prostate cancer. AMG 256, a bifunctional interleukin-21 agonist for PD-1 positive solid tumors."

Enrollment status • Acute Myelogenous Leukemia • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Genito-urinary Cancer • Hematological Malignancies • Oncology • Prostate Cancer • Solid Tumor