Phase 1a/b Study of Monoclonal Antibody CAEL-101 (11-1F4) in Patients with AL Amyloidosis

Blood ◽  
2021 ◽  
Author(s):  
Camille V Edwards ◽  
Nisha Rao ◽  
Divava Bhutani ◽  
Markus Y Mapara ◽  
Jai Radhakrishnan ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Light Chain ◽  
Amyloid Fibrils ◽  
Maximum Tolerated Dose ◽  
Al Amyloidosis ◽  
Open Label ◽  
Serious Adverse Events ◽  
Amyloid Deposits ◽  
Soft Tissue Involvement

Systemic immunoglobulin light-chain (AL) 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 effected their removal via a phagocyte-mediated response. To determine 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 four 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. 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 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.

scholarly journals Mass spectrometry characterization of light chain fragmentation sites in cardiac AL amyloidosis: insights into the timing of proteolysis

2020 ◽  
Vol 295 (49) ◽  
pp. 16572-16584
Author(s):  
Francesca Lavatelli ◽  
Giulia Mazzini ◽  
Stefano Ricagno ◽  
Federica Iavarone ◽  
Paola Rognoni ◽  
...  
Keyword(s):  
Light Chain ◽  
Amyloid Fibrils ◽  
High Specificity ◽  
Al Amyloidosis ◽  
Fragmentation Pattern ◽  
Proteomic Approach ◽  
Amyloid Deposits ◽  
Proteolytic Cleavages ◽  
Al Amyloid

Amyloid fibrils are polymeric structures originating from aggregation of misfolded proteins. In vivo, proteolysis may modulate amyloidogenesis and fibril stability. In light chain (AL) amyloidosis, fragmented light chains (LCs) are abundant components of amyloid deposits; however, site and timing of proteolysis are debated. Identification of the N and C termini of LC fragments is instrumental to understanding involved processes and enzymes. We investigated the N and C terminome of the LC proteoforms in fibrils extracted from the hearts of two AL cardiomyopathy patients, using a proteomic approach based on derivatization of N- and C-terminal residues, followed by mapping of fragmentation sites on the structures of native and fibrillar relevant LCs. We provide the first high-specificity map of proteolytic cleavages in natural AL amyloid. Proteolysis occurs both on the LC variable and constant domains, generating a complex fragmentation pattern. The structural analysis indicates extensive remodeling by multiple proteases, largely taking place on poorly folded regions of the fibril surfaces. This study adds novel important knowledge on amyloid LC processing: although our data do not exclude that proteolysis of native LC dimers may destabilize their structure and favor fibril formation, the data show that LC deposition largely precedes the proteolytic events documentable in mature AL fibrils.

scholarly journals Personalizing Amyloidosis Therapy with Real Time PET Imaging of Fibril-Reactive Monoclonal Antibody Cael-101

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1003-1003 ◽  
Author(s):  
Jing Fu ◽  
Alan Solomon ◽  
Patrick Carberry ◽  
John Castrillon ◽  
Jongho Kim ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Real Time ◽  
Pet Imaging ◽  
Amyloid Fibrils ◽  
Amyloid Fibril ◽  
Systemic Amyloidosis ◽  
Al Amyloidosis ◽  
Amyloid Deposits ◽  
First Time

Abstract Background AL amyloidosis is the most common type of systemic amyloidosis in western countries and has a poor prognosis, with a median survival of 12 to 18 months. Despite the improved prognosis gained by eliminating the offending plasma cell clone, mortality remains high due to multi-organ dysfunction caused by persistent, insoluble amyloid fibril deposits. The amyloid fibril-reactive murine monoclonal antibody 11-1F4 was designed to target amyloid deposits by directly binding to a conformational epitope present on human light-chain amyloid fibrils. The murine form of this antibody has demonstrated potential to bind amyloid in mice and humans (Blood. 2010 116: 2241) and to clear insoluble fibrils in mice with induced human AL amyloidomas, demonstrating the feasibility of using immunotherapy to elicit rapid destruction of amyloid fibrils. Of great translational importance, a chimeric form of 11-1F4 was produced (CAEL-101) and recently demonstrated therapeutic potential in an open-label, dose-escalation phase 1a/b study where 67% of patients with cardiac or renal amyloidosis demonstrated organ response. There was a statistically significant change in Global Longitudinal Strain with 9/10 patients showing improvement (p=0.004). Since we have shown that CAEL-101 successfully improved organ function, the overall goal of this work is for the first time to explore the diagnostic potential of CAEL-101 radiolabeled with a positron emitting radioisotope for systemic amyloidosis as well as to explore its use as a companion biomarker to stratify patients for CAEL-101 immunotherapy. Methods We obtained human amyloid extracts from the heart (κ1), liver (κ1), spleen (λ1) and kidney (λ6). Lyophilized human amyloid extracts were suspended in 25ml of sterile PBS and homogenized for 3 minutes and centrifuged at 12,000g for 30 minutes. 100mg of the resulting pellet was resuspended in sterile saline. Balb/c mice were then injected subcutaneously with amyloid extract. For imaging experiments, cGMP grade CAEL-101 was radiolabeled with 124I, a positron emitting radioisotope used for PET imaging, with the standard iodegen reaction. Approximately 5 days after human amyloid extract was implanted to form subcutaneous amyloidomas, animals were injected with 200μCi of [124I]CAEL-101 and imaged 1 and 4 days post injection using an Inveon microPET scanner. SUVmax for amyloidomas and contralateral background were obtained by drawing regions of interest in the PMOD software package and calculating tumor-to-background (T:B) ratios at 1 and 4 days post tracer infusion. Results We found that [124I]CAEL-101 successfully imaged 100% of mice bearing human amyloid extracts (κ1, λ1 and λ6 subtypes derived from heart, liver, spleen, and kidney). Human amyloidomas were visualized at both at 1 and 4 days post tracer infusion, with significantly increasing T:B radio by day 4, as expected when imaging large molecular weight antibodies. T:B ratios ranged from 2.1 to 4.2 at 4 days. Mice implanted with κ subtypes demonstrated significantly better in vivo T:B ratios (4.1 +/- 0.20), compared to λ subtypes (2.8 +/- 0.46), although all amyloidomas exhibited T:B uptake > 2.1, which would be clinically significant. Conclusions We have demonstrated for the first time the potential of using radiolabeled CAEL-101 as a companion diagnostic to image real-time targeting of human amyloidosis in vivo. This is highly translatable due to the fact that CAEL-101 has shown great promise in early stage clinical trials to clear insoluble amyloid plaques. Importantly, we successfully used PET imaging to visualize cardiac derived amyloid fibrils from AL amyloidosis patients. Therefore, we anticipate that dedicated gated cardiac PET/CT imaging of radiolabeled CAEL-101 will be successful at visualizing cardiac amyloid deposits in patients, especially with the rich blood flow in cardiac tissue and newer generation highly sensitive, high resolution digital PET scanners, in contrast to the non-cardiac optimized whole body scans used in prior studies with antibody-based PET. Given that we were able to image 100% of implanted human amyloidomas derived from heart, spleen, liver and kidney consisting of both κ and λ subtypes, we envision using CAEL-101 PET imaging to (1) diagnose systemic amyloidosis, (2) stratify patients for CAEL-101 immunotherapy, and (3) quantify peripheral organ amyloid fibril deposition pre and post anti-amyloid therapy. Figure Figure. Disclosures Solomon: Caelum Biosciences: Consultancy, Equity Ownership. Lentzsch:Bayer: Consultancy; BMS: Consultancy; Janssen: Consultancy; Caelum Biosciences: Consultancy, Other: Dr. Lentzsch recused herself as an investigator from the Phase 1a/b trial testing CAEL-101 in 11/2017., Patents & Royalties: Shareholder for Caelum Biosiences. Mintz:Caelum Biosciences: Research Funding.

scholarly journals Cryo-EM structure of cardiac amyloid fibrils from an immunoglobulin light chain (AL) amyloidosis patient

2018 ◽  
Author(s):  
Paolo Swuec ◽  
Francesca Lavatelli ◽  
Masayoshi Tasaki ◽  
Cristina Paissoni ◽  
Paola Rognoni ◽  
...  
Keyword(s):  
Light Chain ◽  
Amyloid Fibrils ◽  
Structural Model ◽  
Amino Acid Sequences ◽  
Al Amyloidosis ◽  
Cardiac Amyloid ◽  
Amyloid Deposits ◽  
Target Organs ◽  
Life Threatening ◽  
Domain V

Systemic light chain (AL) amyloidosis is a life-threatening disease caused by aggregation and deposition of monoclonal immunoglobulin light chains (LC) in target organs. Severity of heart involvement is the most important factor determining prognosis. Here, we report the 4.0 Å resolution cryo-electron microscopy (cryo-EM) map and structural model of amyloid fibrils extracted from the heart of an AL patient affected by severe amyloid cardiomyopathy. The fibrils are composed of one asymmetric protofilament, showing typical 4.9 Å stacking and parallel cross-β architecture. Two distinct polypeptide stretches belonging to the LC variable domain (Vl) could be modelled in the density (total of 77 residues), stressing the role of the Vl domain in fibril assembly and LC aggregation. Despite high levels of Vl sequence variability, residues stabilising the observed fibril core are conserved through several Vl domains, highlighting structural motifs that may be common to misfolded LCs. Our data shed first light on the architecture of life-threatening LC amyloid deposits, and provide a rationale for correlating LC amino acid sequences and fibril structures.

Phase I trial of a human-mouse chimeric anti-disialoganglioside monoclonal antibody ch14.18 in patients with refractory neuroblastoma and osteosarcoma.

1998 ◽  
Vol 16 (6) ◽  
pp. 2169-2180 ◽  
Author(s):  
A L Yu ◽  
M M Uttenreuther-Fischer ◽  
C S Huang ◽  
C C Tsui ◽  
S D Gillies ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase I ◽  
Dose Escalation ◽  
Phase I Trial ◽  
Dose Schedule ◽  
Maximum Tolerated Dose ◽  
Target Cells ◽  
Complement Dependent Cytotoxicity ◽  
Clinical Responses

PURPOSE To evaluate the toxicity, immunogenicity, and pharmacokinetics of a human-mouse chimeric monoclonal antibody (mAb) ch 14.18 directed against disialoganglioside (GD2) and to obtain preliminary information on its clinical efficacy, we conducted a phase I trial in 10 patients with refractory neuroblastoma and one patient with osteosarcoma. PATIENTS AND METHODS Eleven patients were entered onto this phase I trial. They received 20 courses of mAb ch 14.18 at dose levels of 10, 20, 50, 100, and 200 mg/m2. Dose escalation was performed in cohorts of three patients; intrapatient dose escalation was also permitted. RESULTS The most prevalent toxicities were pain, tachycardia, hypertension, fever, and urticaria. Most of these toxicities were dose-dependent and rarely noted at dosages of 20 mg/m2 and less. Although the maximum-tolerated dose was not reached in this study, clinical responses were observed. These included one partial (PR) and four mixed responses (MRs) and one stable disease (SD) among 10 assessable patients. Biologic activity of ch 14.18 in vivo was shown by binding of ch 14.18 to tumor cells and complement-dependent cytotoxicity of posttreatment sera against tumor target cells. An anti-ch 14.18 immune response was detectable in seven of 10 patients studied. CONCLUSION In summary, with the dose schedule used, ch 14.18 appears to be clinically safe and effective, and repeated mAb administration was not associated with increased toxicities. Further clinical trials of mAb ch 14.18 in patients with neuroblastoma are warranted.

Studies with Radiolabelled Serum Amyloid P Component Provide Evidence for Turnover and Regression of Amyloid Deposits In Vivo

1994 ◽  
Vol 87 (3) ◽  
pp. 289-295 ◽  
Author(s):  
Philip N. Hawkins
Keyword(s):  
Amyloid Fibrils ◽  
Specific Binding ◽  
Serum Amyloid ◽  
Poor Correlation ◽  
Amyloid P Component ◽  
Serum Amyloid P ◽  
Serum Amyloid P Component ◽  
Amyloid Deposits ◽  
Amyloid P

1. Quantitative scintigraphic and turnover studies, utilizing the specific binding affinity of serum amyloid P component for amyloid fibrils, have been developed as a tool for evaluating amyloid deposits in vivo. 2. Serial studies in over 300 patients have shown characteristic, diagnostic tissue distributions of amyloid in different types of amyloidosis. There is generally a poor correlation between quantity of amyloid and associated organ dysfunction. 3. Contrary to previous expectations, regression of amyloid has been demonstrated systematically for the first time: AA, AL and variant transthyretin-associated amyloid deposits often regress rapidly, and sometimes completely, if the supply of fibril protein precursors is substantially reduced.

scholarly journals A serine protease secreted from Bacillus subtilis cleaves human plasma transthyretin to generate an amyloidogenic fragment

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Daniele Peterle ◽  
Giulia Pontarollo ◽  
Stefano Spada ◽  
Paola Brun ◽  
Luana Palazzi ◽  
...  
Keyword(s):  
Bacillus Subtilis ◽  
Human Plasma ◽  
Amyloid Fibrils ◽  
Wild Type ◽  
Senile Systemic Amyloidosis ◽  
Amyloid Deposits ◽  
Gut Mucosa ◽  
Standard Composition ◽  
Human Wild Type

AbstractAggregation of human wild-type transthyretin (hTTR), a homo-tetrameric plasma protein, leads to acquired senile systemic amyloidosis (SSA), recently recognised as a major cause of cardiomyopathies in 1–3% older adults. Fragmented hTTR is the standard composition of amyloid deposits in SSA, but the protease(s) responsible for amyloidogenic fragments generation in vivo is(are) still elusive. Here, we show that subtilisin secreted from Bacillus subtilis, a gut microbiota commensal bacterium, translocates across a simulated intestinal epithelium and cleaves hTTR both in solution and human plasma, generating the amyloidogenic fragment hTTR(59–127), which is also found in SSA amyloids in vivo. To the best of our knowledge, these findings highlight a novel pathogenic mechanism for SSA whereby increased permeability of the gut mucosa, as often occurs in elderly people, allows subtilisin (and perhaps other yet unidentified bacterial proteases) to reach the bloodstream and trigger generation of hTTR fragments, acting as seeding nuclei for preferential amyloid fibrils deposition in the heart.

scholarly journals Recent Advances in the Diagnosis, Risk Stratification, and Management of Systemic Light-Chain Amyloidosis

2019 ◽  
Vol 141 (2) ◽  
pp. 93-106 ◽  
Author(s):  
Iuliana Vaxman ◽  
Morie Gertz
Keyword(s):  
Plasma Cell ◽  
Light Chain ◽  
Cell Clone ◽  
Proteasome Inhibitors ◽  
Clinical Manifestations ◽  
Al Amyloidosis ◽  
Amyloid Deposits ◽  
Protein Fibrils ◽  
Risk Patients ◽  
Intensive Search

The term amyloidosis refers to a group of disorders in which protein fibrils accumulate in certain organs, disrupt their tissue architecture, and impair the function of the effected organ. The clinical manifestations and prognosis vary widely depending on the specific type of the affected protein. Immunoglobulin light-chain (AL) amyloidosis is the most common form of systemic amyloidosis, characterized by deposition of a misfolded monoclonal light-chain that is secreted from a plasma cell clone. Demonstrating amyloid deposits in a tissue biopsy stained with Congo red is mandatory for the diagnosis. Novel agents (proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, venetoclax) and autologous stem cell transplantation, used for eliminating the underlying plasma cell clone, have improved the outcome for low- and intermediate-risk patients, but the prognosis for high-risk patients is still grave. Randomized studies evaluating antibodies that target the amyloid deposits (PRONTO, VITAL) were recently stopped due to futility and currently there is an intensive search for novel treatment approaches to AL amyloidosis. Early diagnosis is of paramount importance for effective treatment and prognosis, due to the progressive nature of this disease.

Results of a phase I study to evaluate the feasibility, safety, and biological effects of intravenous administration of wild-type reovirus with docetaxel to patients with advanced malignancies

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e13524-e13524
Author(s):  
S. M. Rudman ◽  
C. Comins ◽  
D. Mukherji ◽  
M. Coffey ◽  
K. Mettinger ◽  
...  
Keyword(s):  
Phase I ◽  
Biological Effects ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Wild Type ◽  
Systemic Delivery ◽  
Open Label ◽  
Phase Ii Studies

e13524 Background: Reovirus has minimal pathogenicity in humans but selectively replicates in cells with activated Ras. Wild- type reovirus serotype 3 Dearing strain (Reolysin) has selective antitumor activity in vitro, in murine models, and after systemic delivery in humans in phase 1 trials. Synergistic tumour kill has been observed combining reovirus with taxanes in a range of cancer cell lines and in vivo. Methods: Patients were treated in an open-label, dose-escalating, phase I trial and received 3- weekly 75mg/m2 docetaxel i.v. and reovirus i.v. (day 1–5 of first week inclusive). Reovirus was administered at a starting dose of 3x109 tissue culture infectious dose (TCID50) and then increased to 1 x 1010 and 3 x 1010 TCID50. Primary endpoints were to determine the maximum tolerated dose (MTD), dose limiting toxicity (DLT) and to recommend a dose and schedule for future investigation. Secondary endpoints were to evaluate pharmacokinetics, neutralizing antibody development, cell- mediated immune response and anti-tumour activity. Results: 17 patients were treated (15 males, median age 60 years). No MTD has been reached. DLT's observed were G4 neutropenia (and a recurrent perianal abcess) and G3 rise in AST. Other toxicities observed were fatigue, hypotension and neutropenic sepsis. At present, 5 patients remain on treatment. We have observed 2 partial responses (breast and gastric carcinoma) and 10 patients had stable disease as best response. Conclusions: Reovirus is well tolerated when administered in combination with intravenous docetaxel, with predictable toxicity observed. The recommended dose has been defined at 3x1010 TCID50 and phase II studies are planned. Objective radiological evidence of anticancer activity for this combination has been observed. [Table: see text]

Phase 1 open-label, multiple ascending dose trial of AGEN1884, an anti-CTLA-4 monoclonal antibody, in advanced solid malignancies.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3075-3075
Author(s):  
Breelyn A. Wilky ◽  
Priya Kumthekar ◽  
Robert Wesolowski ◽  
Jimmy J. Hwang ◽  
Jeffrey J. Raizer ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Inhibitory Protein ◽  
Dose Trial ◽  
Dose Levels

3075 Background: AGEN1884 is a fully human IgG1 monoclonal antibody targeting the co-inhibitory protein cytotoxic T lymphocyte-associated protein 4 (CTLA-4). CTLA-4 blockade has been shown to augment T cell activation and proliferation, resulting in immune infiltration of the tumor and subsequent regression. Objectives: Assess the safety, maximum tolerated dose (MTD), and pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of AGEN1884 in patients (pts) with advanced and refractory malignancies using a “3+3” trial design. Methods: Eleven pts have been enrolled and treated to date. AGEN1884 was administered intravenously q3w for 4 doses and then q12w. Three (0.1, 0.3 and 1 mg/kg) of six (3, 6 and 10 mg/kg) planned dose levels have been completed. Results: Five pts were accrued at 0.1 mg/kg dose level (2 were not DLT evaluable) and three pts each at doses of 0.3 mg/kg and 1 mg/kg. Median age was 56 years (range 26–70), ECOG 0–2, with a median of 4 (range 1–8) prior therapies. No DLT events have been observed thus far. Data from 5 pts were available for PK evaluation. Half-life of AGEN1884 post first dose was 8.8 and 9.6 days for 0.3 mg/kg and 0.1 mg/kg dose levels, respectively, as measured by ELISA. As of Jan 31, 2017, pts across cohorts were followed for a median of 6 weeks (range 0-28). Six pts (54.5%) have come off study due to disease progression, while 5 (45.5 %) remain on study. One confirmed partial response (80% reduction) by RECIST criteria was seen at 0.1 mg/kg in a patient with angiosarcoma. Conclusions: AGEN1884 is safe at 0.1 and 0.3 mg/kg dose levels. Dose escalation is ongoing and updated safety and PK data will be presented. Clinical trial information: NCT02694822.

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