A5078061615- Monoclonal and Polyclonal Antibodies Research
- HER2/EGFR in Cancer Research
- Synthesis and pharmacology of benzodiazepine derivatives
- Genetics and Neurodevelopmental Disorders
- Diamond and Carbon-based Materials Research
- Radiopharmaceutical Chemistry and Applications
- Nuclear Receptors and Signaling
- Gyrotron and Vacuum Electronics Research
- Glycosylation and Glycoproteins Research
- Particle accelerators and beam dynamics
- Cancer therapeutics and mechanisms
- Prostate Cancer Treatment and Research
- Protein Degradation and Inhibitors
- Multiple Myeloma Research and Treatments
- Neuroscience and Neuropharmacology Research
- PARP inhibition in cancer therapy
- Immune Cell Function and Interaction
- Ion-surface interactions and analysis
- Cancer Treatment and Pharmacology
- CAR-T cell therapy research
- Particle Accelerators and Free-Electron Lasers
- Protein purification and stability
- 14-3-3 protein interactions
- Semiconductor materials and devices
- Carbon Nanotubes in Composites
Boston Children's Hospital
2021-2025
AstraZeneca (United States)
2019-2023
Los Alamos National Laboratory
1979-2022
A new antibody platform combining anti-Psl and anti-PcrV activities provides enhanced protection acts synergistically with antibiotics against Pseudomonas aeruginosa .
Abstract The EphA2 receptor tyrosine kinase is selectively expressed on the surface of many different human tumors. We have previously shown that tumor cells can be targeted by monoclonal antibodies and these function, in part, inducing internalization degradation. In this report, we describe isolation characterization a fully antibody (1C1) binds both rodent receptor. After cell binding, induces rapid phosphorylation, internalization, degradation Because bind internalize provide vehicle for...
Immunogenic cell death (ICD) is the process by which certain cytotoxic drugs induce apoptosis of tumor cells in a manner that stimulates immune system. In this study, we investigated whether antibody-drug conjugates (ADCS) conjugated with pyrrolobenzodiazepine dimer (PBD) or tubulysin payloads ICD, modulate microenvironment, and could combine immuno-oncology to enhance antitumor activity. We show these on their own induced an response prevented growth tumors following subsequent challenge....
Antibody–drug conjugates (ADCs) are a class of biopharmaceuticals that combine the specificity antibodies with high-potency cytotoxic drugs. Engineering cysteine residues in using mutagenesis is common method to prepare site-specific ADCs. With this approach, solvent accessible amino acids antibody have been selected for substitution conjugating maleimide-bearing drugs, resulting homogeneous and stable Here we describe engineering approach based on insertion cysteines before after sites...
Undesired solution behaviors such as reversible self-association (RSA), high viscosity, and liquid-liquid phase separation can introduce substantial challenges during development of monoclonal antibody formulations. Although a global mechanistic understanding RSA (i.e., native protein-protein interactions) is sufficient to develop robust formulation controls, its mitigation via protein engineering requires knowledge the sites interactions. In study reported here, we coupled our previous...
Abstract De novo and acquired drug resistance can limit the long-term efficacy of targeted cancer therapies such as tyrosine kinase inhibitors targeting key oncogenic drivers like EGFR cMET. Mechanisms include secondary mutations cMET other downstream pathways KRAS amplification alternate growth factor receptors. MET or protein overexpression has been established most common mechanism clinical to osimertinib. AZD9592 is a first-in-class bispecific ADC designed target cMET, while overcoming...
Tissue-specific T cell immune responses play a critical role in maintaining organ health but can also drive pathology during both autoimmunity and alloimmunity. The mechanisms controlling intratissue programming remain unclear. Here, we leveraged nonhuman primate model of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem transplantation to probe the biological underpinnings tissue-specific alloimmune using comprehensive systems immunology approach including...
Immunosuppression in solid organ transplant recipients inhibits protective immune responsiveness to pathogens and vaccines. However, specific cell states that associate with failure generate immunity are not known. Here, we perform scRNAseq CyTOF analyses of PBMC from 12 pediatric 8 healthy children revealing the full spectrum present these individuals, examine association generation humoral cellular following vaccination. We determined clonal expansion a subset CD8+ effector T cells is...
Targeted nanomedicines are a promising technology for treatment of disease; however, preparation and characterization well-defined protein-nanoparticle systems remain challenging. Here, we describe platform to prepare antibody binding fragment (Fab)-bearing nanoparticles an accompanying real-time cell-based assay determine their cellular uptake compared monoclonal antibodies (mAbs) Fabs. The nanoparticle was composed core-cross-linked polyion complex (PIC) micelles prepared from...
Abstract B cell activation is regulated by a variety of signals. CD19 positively regulates activation, augmenting signals delivered through the BCR complex. In contrast, CD32b contains an ITIM and negatively signaling. Importantly, there are drugs currently in clinical trials preclinical development that cross-link to molecules within We wanted address how single engagement versus cotargeting these affects human function. When cells from healthy individuals were activated mimic T response...
Abstract Antibody–drug conjugates (ADC) are used to selectively deliver cytotoxic agents tumors and have the potential for increased clinical benefit cancer patients. 5T4 is an oncofetal antigen overexpressed on cell surface in many carcinomas both bulk tumor cells as well stem (CSC), has very limited normal tissue expression, can internalize when bound by antibody. An anti-5T4 antibody was identified optimized efficient binding internalization a target-specific manner, engineered cysteines...
Abstract Prostate-specific membrane antigen (PSMA) is a membrane-bound glutamate carboxypeptidase that highly expressed in nearly all prostate cancers with the highest expression metastatic castration-resistant cancer (mCRPC). The prevalence of increased surface and constitutive internalization PSMA make it an attractive target for antibody–drug conjugate (ADC) approach to treating patients mCRPC. MEDI3726 (previously known as ADCT-401) ADC consisting engineered version anti-PSMA antibody...
Antibody–drug conjugates (ADCs) have become a powerful platform to deliver cytotoxic agents selectively cancer cells. ADCs traditionally been prepared by stochastic conjugation of drug using an antibody's native cysteine or lysine residues. Through strategic selection the mammalian expression host, we were able introduce azide-functionalized glycans onto homogeneously glycosylated anti-EphA2 monoclonal antibody in one step. Conjugation with alkyne-bearing pyrrolobenzodiazepine dimer payload...
Abstract Resistance to antibody–drug conjugates (ADCs) has been observed in both preclinical models and clinical studies. However, mechanisms of resistance pyrrolobenzodiazepine (PBD)-conjugated ADCs have not well characterized thus, this study was designed investigate development PBD dimer warheads PBD-conjugated ADCs. We established a PBD-resistant cell line, 361-PBDr, by treating human breast cancer MDA-MB-361 cells with gradually increasing concentrations SG3199, the released from...
Antibody-drug conjugates (ADCs) have emerged as an important class of therapeutics for cancer treatment that combine the target specificity antibodies with killing activity anticancer chemotherapeutics. Early conjugation technologies relied upon random to either lysine or cysteine residues, resulting in heterogeneous ADCs. Recent technology advancements resulted preparation homogeneous ADCs through site-specific at engineered cysteines, glycosylated amino acids, and bioorthogonal unnatural...
Targeting Eph (erythropoietin producing hepatoma) receptors with monoclonal antibodies is being explored as therapy for several types of cancer. To test whether simultaneous targeting EphA2, EphA4, and EphB4 would be an effective approach to cancer therapy, we generated a recombinant trispecific antibody using the variable domain genes anti-EphA2, anti-EphA4, anti-EphB4 antibodies. A multidisciplinary combining biochemical, biophysical, cellular-based assays was used characterize in vitro...
Thiosuccinimide-linked antibody-drug conjugates (ADCs) are susceptible to drug loss over time due a retro-Michael reaction, which can be prevented by selecting stable conjugation positions or hydrolysis of the thiosuccinimide. Here, we investigate pyrrolobenzodiazepine (PBD) ADC drug-linkers equipped with N-phenyl maleimide functionality for thiol via thiosuccinimide hydrolysis. Two PBD drug-linker formats (enzyme-cleavable and non-cleavable) were evaluated following site-specific an...
By simultaneous binding two disease mediators, bispecific antibodies offer the opportunity to broaden utility of antibody-based therapies. Herein, we describe design and characterization Bs4Ab, an innovative generic tetravalent antibody platform. The Bs4Ab format comprises a full-length IgG1 monoclonal with scFv inserted into hinge domain. demonstrates robust manufacturability as evidenced by MEDI3902, which is currently in clinical development. To further demonstrate applicability...