Interim analysis of the phase 1a/b study of chimeric fibril-reactive monoclonal antibody 11-1F4 in patients with AL amyloidosis

Edwards, Camille V; Gould, Julia; Langer, Arielle L; Mapara, Markus Y.; Radhakrishnan, Jai; Maurer, Mathew S.; Raza, Shahzad; Mears, JG; Wall, Jonathan S.; Solomon, Alan; Lentzsch, Suzanne

doi:10.1080/13506129.2017.1292900

Cited by 55 publications

(46 citation statements)

References 4 publications

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“…In support, the chimeric fibril-reactive monoclonal antibody can be used in patients with light chain-associated amyloidosis to identify candidates for passive immunotherapy. 10,11 Daratumumab (Dara), a human anti-CD38 immunoglobulin G 1 (ĸ subclass) antibody against the highly expressed plasma cell receptor CD38, has shown particularly efficacious clinical activity [12][13][14][15][16] and recently has been approved by the US Food and Drug Administration for the treatment of relapsed MM. Because almost all MM patients express CD38 on the surface of their cancer cells, we hypothesize that tracing MM cell dissemination by targeting CD38 could be a successful approach.…”

Section: Introductionmentioning

confidence: 99%

Copper 64–labeled daratumumab as a PET/CT imaging tracer for multiple myeloma

Caserta

Chea²,

Minnix³

et al. 2018

Blood

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As a growing number of patients with multiple myeloma (MM) respond to upfront therapies while eventually relapsing in a time frame that is often unpredictable, attention has increasingly focused on developing novel diagnostic criteria to also account for disease dissemination. Positron emission tomography/computed tomography (PET/CT) is often used as a noninvasive monitoring strategy to assess cancer cell dissemination, but because the uptake of the currently used radiotracer 18fluorodeoxyglucose (F-FDG) is a function of the metabolic activity of both malignant and nonmalignant cells, the results frequently lack sufficient specificity. Radiolabeled antibodies targeting MM tissue may detect disease irrespective of cell metabolism. Hence, we conjugated the clinically significant CD38-directed human antibody daratumumab (Darzalex [Dara]) to the DOTA chelator and labeled it with the positron-emitting radionuclide copper 64 (Cu; Cu-DOTA-Dara). Here, we show thatCu-DOTA-Dara can efficiently bind CD38 on the surface of MM cells and was mainly detected in the bones associated with tumor in a MM murine model. We also show that PET/CT based on Cu-DOTA-Dara displays a higher resolution and specificity to detect MM cell dissemination than doesF-FDG PET/CT and was even more sensitive than were bioluminescence signals. We therefore have supporting evidence for using Cu-DOTA-Dara as a novel imaging agent for MM.

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Section: Introductionmentioning

confidence: 99%

Copper 64–labeled daratumumab as a PET/CT imaging tracer for multiple myeloma

Caserta

Chea²,

Minnix³

et al. 2018

Blood

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“…IIb placebo-controlled trial failed to confirm the positive effects of NEOD001 on cardiac involvement, and the development of this antibody was discontinued. This emphasizes the need of controlled studies based on robust endpoints to introduce novel therapies for AL amyloidosis.The murine monoclonal antibody 11-1F4 recognizes an amyloid-associated conformational epitope in human light chain-related fibrils150 . In studies of mice with human amyloidomas (soft tissue tumors of AL composition created in the hindquarters of mice)11-1F4 induced a rapid reduction of the masses without toxicity151 .…”

mentioning

confidence: 99%

Systemic immunoglobulin light chain amyloidosis

Merlini

Dispenzieri

Sanchorawala

et al. 2018

Nat Rev Dis Primers

407

387

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Systemic immunoglobulin light chain (AL) amyloidosis is a protein misfolding disease that is caused by the conversion of immunoglobulin light chains from their soluble functional states into highly organized amyloid fibrillar aggregates that lead to organ dysfunction. The disease is progressive and, accordingly, early diagnosis is vital to prevent irreversible organ damage, of which cardiac and renal damage predominate. The development of novel sensitive biomarkers and imaging technologies for the detection and quantification of organ involvement and damage are facilitating earlier diagnosis and enhanced evaluation of the efficacy of new and existing therapies. Treatment is guided by risk assessment which is based on levels of cardiac biomarkers; close monitoring of clonal and organ response guides duration of therapy and changes in regimen. Several new classes of drugs, such as proteasome inhibitors and immunomodulatory drugs, along with high-dose chemotherapy and autologous haematopoietic stem cell transplantation, have led to rapid and deep suppression of the amyloid light chain production in the majority of patients. However, effective therapies for patients with advanced cardiac involvement are an unmet need. Passive immunotherapies targeting clonal plasma cells and directly accelerating removal of amyloid deposits promise to further improve the overall outlook of this increasingly treatable disease.

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“…The study demonstrated overall organ response of 63% (14/24), 67% (8/12) cardiac response, and 50% (5/10) renal response 54 . The median times to response were 21 and 28 days in cardiac and renal amyloid, respectively.…”

Section: Treatmentmentioning

confidence: 86%

Recent advances in understanding and treating immunoglobulin light chain amyloidosis

2018

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Immunoglobulin (Ig) light chain (AL) amyloidosis is a clonal plasma cell disorder characterized by misfolded Ig light chain deposition in vital organs of the body, resulting in proteotoxicity and organ dysfunction. Owing to its diverse clinical presentations and a tendency to mimic common medical conditions, AL amyloidosis is often diagnosed late and results in dismal outcomes. Early referral to a specialized center with expertise in management of AL amyloidosis is always recommended. The availability of sensitive biomarkers and novel therapies is reforming our approach to how we manage AL amyloidosis. Treatment for patients with AL amyloidosis should be risk-adapted and customized on the basis of individual patient characteristics. In the future, approaches directed at amyloid fibril clearance in combination with agents that target plasma cells will be needed both to eradicate the malignant clone and to establish organ responses.

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Interim analysis of the phase 1a/b study of chimeric fibril-reactive monoclonal antibody 11-1F4 in patients with AL amyloidosis

Cited by 55 publications

References 4 publications

Copper 64–labeled daratumumab as a PET/CT imaging tracer for multiple myeloma

Copper 64–labeled daratumumab as a PET/CT imaging tracer for multiple myeloma

Systemic immunoglobulin light chain amyloidosis

Recent advances in understanding and treating immunoglobulin light chain amyloidosis

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