Immunogenicity of Monoclonal Antibodies and the Potential Use of HLA Haplotypes to Predict Vulnerable Patients

Mosch, Romy; Guchelaar, Henk‐Jan

doi:10.3389/fimmu.2022.885672

Cited by 21 publications

(15 citation statements)

References 133 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Formation of antidrug antibodies have previously been shown to contribute to loss of efficacy, 25 however the clinical impact of the antidrug antibodies observed in this cohort remain uncertain since neutralizing assays were not performed. The pharmacodynamic data were consistent with previous assessments for cusatuzumab and support its mechanism of action to reduce AML blasts and decrease serum sCD27 levels.…”

Section: Discussionmentioning

confidence: 91%

Results from a phase I/II trial of cusatuzumab combined with azacitidine in patients with newly diagnosed acute myeloid leukemia who are ineligible for intensive chemotherapy

et al. 2023

View full text Add to dashboard Cite

Cusatuzumab is a high-affinity, anti-CD70 monoclonal antibody under investigation in AML. This two-part, open-label, multicenter, phase I/II trial evaluated cusatuzumab plus azacitidine in patients with newly diagnosed AML ineligible for intensive chemotherapy. Patients received a single dose of cusatuzumab at one of four dose levels (1, 3, 10, or 20 mg/kg), 14 days before starting combination therapy. In phase I dose-escalation, cusatuzumab was then administered on days 3 and 17, in combination with azacitidine (75 mg/m2) on days 1-7, every 28 days. Primary objective in phase I was to determine the recommended phase II dose (RP2D) of cusatuzumab plus azacitidine. Phase II primary objective was efficacy at the RP2D (selected as 10 mg/kg). Thirty-eight patients enrolled: 12 in phase I (three per dose level; four with ELN adverse risk) and 26 in phase II (21 with adverse risk). Objective response (≥ partial remission) was achieved by 19/38 patients (including 8/26 in phase II); 14/38 achieved complete remission. Eleven patients (37.9%) achieved objective response among the 29 patients in phase I and phase II treated at the RP2D. At median follow-up of 10.9 months, median duration of first response was 4.5 months and median overall survival was 11.5 months. Most common treatment-emergent adverse events were infections (84.2%) and hematologic toxicities (78.9%). Seven patients (18.4%) reported infusion-related reactions, including two with grade 3 events. Thus, cusatuzumab/azacitidine appears generally well tolerated and shows preliminary efficacy in this setting. Investigation of cusatuzumab combined with current standard-of-care therapy, comprising venetoclax and azacitidine, is ongoing.

show abstract

Section: Discussionmentioning

confidence: 91%

Results from a phase I/II trial of cusatuzumab combined with azacitidine in patients with newly diagnosed acute myeloid leukemia who are ineligible for intensive chemotherapy

et al. 2023

View full text Add to dashboard Cite

show abstract

“…Antidrug antibodies (ADA) are produced by the immune system in response to the presence of a foreign substance such as a biotherapeutic protein. ADA may not only neutralize the therapeutic effects of the drug but also cause immune-related adverse events. − Therefore, monitoring and managing ADA are critical to ensuring the effectiveness of the drug as well as the safety of patients. The risk for unwanted immune responses or immunogenicity of 20 different Q-tags (Table S9) inserted at 9 different positions (HC118, HC177, HC297, HC341, HC401, HC446, LC110, LC143, and LC214) of an unconjugated anti-HER2 human IgG1 antibody was evaluated.…”

Section: Resultsmentioning

confidence: 99%

Diligent Design Enables Antibody-ASO Conjugates with Optimal Pharmacokinetic Properties

Sela,

Mansø,

Siegel

et al. 2023

Bioconjugate Chem.

View full text Add to dashboard Cite

Antisense-oligonucleotides (ASOs) are a promising drug modality for the treatment of neurological disorders, but the currently established route of administration via intrathecal delivery is a major limitation to its broader clinical application. An attractive alternative is the conjugation of the ASO to an antibody that facilitates access to the central nervous system (CNS) after peripheral application and target engagement at the blood–brain barrier, followed by transcytosis. Here, we show that the diligent conjugate design of Brainshuttle-ASO conjugates is the key to generating promising delivery vehicles and thereby establishing design principles to create optimized molecules with drug-like properties. An innovative site-specific transglutaminase-based conjugation technology was chosen and optimized in a stepwise process to identify the best-suited conjugation site, tags, reaction conditions, and linker design. The overall conjugation performance was found to be specifically governed by the choice of buffer conditions and the structure of the linker. The combination of the peptide tags YRYRQ and RYESK was chosen, showing high conjugation fidelity. Elaborate conjugate analysis revealed that one leading differentiating factor was hydrophobicity. The increase of hydrophobicity by the ASO payload could be mitigated by the appropriate choice of conjugation site and the heavy chain position 297 proved to be the most optimal. Evaluating the properties of the linker suggested a short bicyclo[6.1.0]nonyne (BCN) unit as best suited with regards to conjugation performance and potency. Promising in vitro activity and in vivo pharmacokinetic behavior of optimized Brainshuttle-ASO conjugates, based on a microtubule-associated protein tau (MAPT) targeting oligonucleotide, suggest that such designs have the potential to serve as a blueprint for peripherally delivered ASO-based drugs for the CNS in the future.

show abstract

“…Some factors, such as smoking, infections, antibiotics, and immunosuppressants, are related to antidrug antibody formation in autoimmune diseases [ 19 ]. However, genetic factors have a very important role in antidrug antibody formation [ 19 ], with HLA haplotypes being one of the most promising for predicting patients at risk of immunogenicity [ 20 ]. The MHC region contains more than 250 genes (including some HLA genes among them), and linkage disequilibrium blocks of up to 3 Mb are frequent.…”

Section: Discussionmentioning

confidence: 99%

Association between HLA DNA Variants and Long-Term Response to Anti-TNF Drugs in a Spanish Pediatric Inflammatory Bowel Disease Cohort

Salvador-Martín

Zapata-Cobo

Velasco

et al. 2023

IJMS

View full text Add to dashboard Cite

The genetic polymorphisms rs2395185 and rs2097432 in HLA genes have been associated with the response to anti-TNF treatment in inflammatory bowel disease (IBD). The aim was to analyze the association between these variants and the long-term response to anti-TNF drugs in pediatric IBD. We performed an observational, multicenter, ambispective study in which we selected 340 IBD patients under 18 years of age diagnosed with IBD and treated with anti-TNF drugs from a network of Spanish hospitals. Genotypes and failure of anti-TNF drugs were analyzed using Kaplan-Meier curves and Cox logistic regression. The homozygous G allele of rs2395185 and the C allele of rs2097432 were associated with impaired long-term response to anti-TNF drugs in children with IBD after 3 and 9 years of follow-up. Being a carrier of both polymorphisms increased the risk of anti-TNF failure. The SNP rs2395185 but not rs2097432 was associated with response to infliximab in adults with CD treated with infliximab but not in children after 3 or 9 years of follow-up. Conclusions: SNPs rs2395185 and rs2097432 were associated with a long-term response to anti-TNFs in IBD in Spanish children. Differences between adults and children were observed in patients diagnosed with CD and treated with infliximab.

show abstract

Immunogenicity of Monoclonal Antibodies and the Potential Use of HLA Haplotypes to Predict Vulnerable Patients

Cited by 21 publications

References 133 publications

Results from a phase I/II trial of cusatuzumab combined with azacitidine in patients with newly diagnosed acute myeloid leukemia who are ineligible for intensive chemotherapy

Results from a phase I/II trial of cusatuzumab combined with azacitidine in patients with newly diagnosed acute myeloid leukemia who are ineligible for intensive chemotherapy

Diligent Design Enables Antibody-ASO Conjugates with Optimal Pharmacokinetic Properties

Association between HLA DNA Variants and Long-Term Response to Anti-TNF Drugs in a Spanish Pediatric Inflammatory Bowel Disease Cohort

Contact Info

Product

Resources

About