Discovery of INCA033989, a Monoclonal Antibody That Selectively Antagonizes Mutant Calreticulin Oncogenic Function in Myeloproliferative Neoplasms (MPNs)

Buonpane, Rebecca A.; Celik, Hamza; Marty, Caroline; Lei, Angela; Jobe, Fatoumata; Rupar, Mark; Zhang, Yue; DiMatteo, Darlise; Awdew, Rahel; Vainchenker, William; Zhou, Jing; Hitchcock, Ian S.; Plo, Isabelle; Nastri, Horacio; Mayes, Patrick A.

doi:10.1182/blood-2022-159435

Cited by 21 publications

(22 citation statements)

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“…On the other hand, AHSCT in MF is a disease‐modifying treatment modality that deserves more attention in terms of current research direction and budget allocation. Finally, I am intrigued by the preliminary observations from preclinical studies of mutant CALR‐specific monoclonal antibody and eagerly await its evaluation in formal clinical trials 118 …”

Section: Closing Remarksmentioning

confidence: 99%

Primary myelofibrosis: 2023 update on diagnosis, risk‐stratification, and management

Tefferi

2023

American J Hematol

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Disease Overview Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by stem cell‐derived clonal myeloproliferation that is often but not always accompanied by JAK2, CALR, or MPL mutations; additional features include bone marrow reticulin/collagen fibrosis, aberrant inflammatory cytokine expression, anemia, hepatosplenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, risk of leukemic progression, and shortened survival. Diagnosis Bone marrow examination with cytogenetic and mutation studies provides integrated diagnostic information; presence of JAK2, CALR or MPL mutation is expected but not required. New Classification System The International Consensus Classification distinguishes “prefibrotic” from “overtly fibrotic” PMF; the former might mimic essential thrombocythemia (ET) in its presentation. Approximately 15% of patients with ET or polycythemia vera (PV) might progress into post‐ET/PV MF. Mutations SRSF2, ASXL1, and U2AF1‐Q157 mutations predict inferior survival in PMF; RAS/CBL mutations predict resistance to ruxolitinib therapy. Type 1/like CALR mutation is associated with superior survival. Karyotype Very high‐risk abnormalities include −7, inv (3), i(17q), +21, +19, 12p‐ and 11q‐. Favorable risk abnormalities include normal karyotype or isolated +9, 13q‐, 20q‐, 1q abnormalities and loss of Y chromosome. Risk Stratification Contemporary prognostic systems include GIPSS (genetically‐inspired prognostic scoring system) and MIPSS70+ version 2.0 (MIPSSv2; mutation‐and karyotype‐enhanced international prognostic scoring system). GIPSS is based exclusively on mutations and karyotype; MIPSSv2 includes, in addition, clinical risk factors. Risk‐Adapted Therapy Observation alone is advised for MIPSSv2 “low” and “very low” risk disease (estimated 10‐year survival 56%–92%); allogeneic hematopoietic stem cell transplant (AHSCT) is the preferred treatment of choice for “very high” and “high” risk disease (estimated 10‐year survival 0–13%), as well as in carefully selected patients with intermediate‐risk disease (estimated 10‐year survival 30%). Drug therapy in MF is currently palliative and targets anemia, splenomegaly, and constitutional symptoms. JAK2 Inhibitors Ruxolitinib, fedratinib, and pacritinib are FDA approved and respectfully utilized in patients failing treatment with hydroxyurea, ruxolitinib, or with platelet count <50 × 10 (9)/L. Momelotinib is another JAK2 inhibitor that is poised for approval sometime in 2023 and has shown erythropoietic benefits, in addition to affecting spleen and symptom responses. Other Treatment Modalities Splenectomy is considered for drug‐refractory splenomegaly and involved field radiotherapy for non‐hepatosplenic EMH and extremity bone pain. New Directions New agents, alone or in combination with ruxolitinib, are currently under clinical trial investigation (ClinicalTrials.gov) and preliminary results were presented at the 2022 ASH annual meeting and highlighted in the current review.

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Section: Closing Remarksmentioning

confidence: 99%

Primary myelofibrosis: 2023 update on diagnosis, risk‐stratification, and management

Tefferi

2023

American J Hematol

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“… 136 Similar findings in primary MPN cells were recently reported for a fully human immunoglobulin G1–mutant CALR antibody (INCA033989) as a plenary abstract at the 2022 American Society of Hematology meeting. 139 In addition, using a chimeric mutant CALR BM transplant model, the authors reported that treatment with INCA033989 selectively targeted CALR -mutant platelets, megakaryocytes, and long-term HSCs. In aggregate, these preclinical studies indicate that therapeutic mutant CALR antibodies have specificity and efficacy, and further clinical development is awaited.…”

Section: Calr-mutated Mpns Provide Novel Therapeutic Targetsmentioning

confidence: 99%

Biology and therapeutic targeting of molecular mechanisms in MPNs

How

Garcia

Mullally

2023

Blood

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Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by activated Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling. As a result, JAK inhibitors have been the standard therapy to treat myelofibrosis (MF) patients. Although currently approved JAK inhibitors successfully ameliorate MPN-related symptoms, they are not known to substantially alter the MF disease course. Similarly, in essential thrombocythemia (ET) and polycythemia vera (PV), treatments are primarily aimed at reducing the risk of cardiovascular and thromboembolic complications, with a watchful waiting approach often used in patients who are considered lower risk for thrombosis. However, better understanding of MPN biology has led to the development of rationally designed therapies, with the goal of not only addressing disease complications, but also potentially modifying disease course. We review the most recent data elucidating mechanisms of disease pathogenesis, and highlight emerging therapies that target MPN on several biologic levels, including JAK2-mutant MPN stem cells, JAK and non-JAK signaling pathways, mutant calreticulin and the inflammatory bone marrow microenvironment.

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“…84 Antibody strategies have been developed and showed very promising results in preclinical studies. 84 A 'silent-Fc' antibody to block the CALR-MPL interaction has also been developed and will enter a phase I clinical trial, initially in chronic phase disease. CART cell therapy or BiTE approaches are also feasible and under evaluation in the preclinical setting.…”

Section: M Mu Noth Er a Py A N D Ce L Lu L A R Th Er A Py A Pproach E Smentioning

confidence: 99%

“…CALR MUT , as discussed above, is an appealing immunotherapeutic target, resulting from a frameshift mutation that leads to a novel C Terminus which is absent in other cells. Additionally, CALR MUT is expressed on the cell surface by binding to the thrombopoietin (TPO) receptor 84 . Antibody strategies have been developed and showed very promising results in preclinical studies 84 .…”

Section: Immunotherapy and Cellular Therapy Approachesmentioning

confidence: 99%

“…Additionally, CALR MUT is expressed on the cell surface by binding to the thrombopoietin (TPO) receptor 84 . Antibody strategies have been developed and showed very promising results in preclinical studies 84 . A ‘silent‐Fc’ antibody to block the CALR‐MPL interaction has also been developed and will enter a phase I clinical trial, initially in chronic phase disease.…”

Section: Immunotherapy and Cellular Therapy Approachesmentioning

confidence: 99%

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Updates on accelerated and blast phase myeloproliferative neoplasms: Are we making progress?

Mahdi,

Spiers,

Rampotas

et al. 2023

Br J Haematol

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SummaryManagement approaches for accelerated and blast phase myeloproliferative neoplasms remain challenging for clinicians and patients alike. Despite many therapeutic advances, outcomes for those patients who are not allogeneic haematopoietic cell transplant eligible remain, in general, very poor. Estimated survival rates for such blast phase patients is frequently reported as less than 6 months. No specific immunological, genomic or clinicopathological signature currently exists that accurately predicts the risk and timing of transformation, which frequently induces a high degree of anxiety among patients and clinicians alike. Within this review article, we provide an up‐to‐date summary of current understanding of the underlying pathogenesis of accelerated and blast phase disease and discuss current therapeutic approaches and realistic outcomes. Finally, we discuss how the horizon may look with the introduction of more novel agents into the clinical arena.

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Discovery of INCA033989, a Monoclonal Antibody That Selectively Antagonizes Mutant Calreticulin Oncogenic Function in Myeloproliferative Neoplasms (MPNs)

Cited by 21 publications

References 0 publications

Primary myelofibrosis: 2023 update on diagnosis, risk‐stratification, and management

Primary myelofibrosis: 2023 update on diagnosis, risk‐stratification, and management

Biology and therapeutic targeting of molecular mechanisms in MPNs

Updates on accelerated and blast phase myeloproliferative neoplasms: Are we making progress?

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