Phase 1a/b study of monoclonal antibody CAEL-101 (11-1F4) in patients with AL amyloidosis

Abstract

Systemic immunoglobulin light-chain amyloidosis is characterized by pathologic deposition of immunoglobulin light chains as amyloid fibrils in vital organs, leading to organ impairment and eventual death. That the process is reversible was evidenced in an in vivo experimental model in which fibril-reactive chimeric monoclonal antibody (mAb) 11-1F4 directly targeted human light-chain amyloid deposits and affected their removal via a phagocyte-mediated response. To determine the tolerability and potential amyloidolytic effect of this agent (now designated mAb CAEL-101), we conducted a phase 1a/b study involving 27 patients, most of whom had manifestations of organ involvement. This was an open-label study in which phase 1a patients received mAb CAEL-101 as a single intravenous infusion with escalating dose levels from 0.5 mg/m2 to 500 mg/m2 to establish the maximum tolerated dose (MTD). In phase 1b, the antibody was administered as a graded series of 4 weekly infusions. For both phases, there were no drug-related serious adverse events or dose-limiting toxicities among recipients, and the MTD was not reached. The majority of patients had deep hematologic responses but persistent organ disease prior to treatment. Fifteen of 24 patients (63%) who manifested cardiac, renal, hepatic, gastrointestinal, or soft tissue involvement had a therapeutic response to mAb CAEL-101 as evidenced by serum biomarkers or objective imaging modalities with a median time to response of 3 weeks. Infusions of mAb CAEL-101 were well tolerated and, for the majority, resulted in improved organ function, notably for those with cardiac impairment. This trial was registered at www.clinicaltrials.gov as #NCT02245867.

© 2021 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Mean (SE) PK profiles for mAb CAEL-101 in single ascending dose cohorts by dose level on linear and log-linear scales (phase 1a).

Figure 2.

Mean (SE) PK profiles for mAb CAEL-101 in multiple ascending dose cohorts by dose level on linear and log-linear scales (phase 1b).

Figure 3.

Analysis of percentage change in NT-proBNP from baseline in cardiac-evaluable patients (baseline NT-proBNP of ≥650 pg/mL and at least 1 postbaseline NT-proBNP measurement). Cardiac responders are denoted with deep blue bars (>30% and >300 pg/mL decrease in NT-proBNP). No cardiac progressors (>30% and >300 pg/mL increase in NT-proBNP) were identified. Cardiac stable patients are denoted with light blue bars (neither response nor progression). For each individual patient, time since last exposure to antiplasma cell therapy (months), light chain disease type (κ or λ), and hematologic disease status at the time of study enrollment is reported.

Figure 4.

Changes in global longitudinal strain with mAb CAEL-101 in patients with cardiac involvement enrolled in phase 1b (n = 10; blue lines). This figure highlights cardiac response assessment based on measurement of myocardial function at baseline and week 12 using speckle-tracking (TomTec-Arena 1.2) and calculated as an average of 4-, 2-, and 3- chamber based measurements in cardiac response evaluable patients. Nineteen patients were enrolled in the phase 1b study and 10/19 patients were evaluable for cardiac response. NT-proBNP (pg/mL) is included for each patient at baseline (left) and at week 12 (right). An improvement of 2 units (a decrease by −2) is a clinically significant improvement in strain in the AL amyloidosis population. Mean GLS improved significantly in 9/10 patients from −15.58% ± −4.14% at screening to −17.37% ± −3.53% at week 12, P = .004. Pearson correlation coefficient between NT-proBNP response and GLS response (in 8 cardiac evaluable patients) was 0.345, which supports correlation of 2 markers of organ response.

Figure 5.

Analysis of best response of percentage change in 24-hour urine protein from baseline in renal-evaluable patients (baseline 24-hour urine protein of >500 mg/24 h and at least 1 postbaseline 24-hour urine protein measurement). Renal responders are denoted with deep blue bars (≥30% decrease in proteinuria or fall in 24-hour urine protein below 500 mg/24 h). Renal stable patients are denoted with light blue bars (neither response nor progression). Renal progressors are denoted by red bars (≥25% decrease in eGFR). For each individual patient, time since last exposure to antiplasma cell therapy (months), light chain disease type (κ or λ), and hematologic disease status at the time of study enrollment is reported.