A5006463781- Monoclonal and Polyclonal Antibodies Research
- Multiple Myeloma Research and Treatments
- Synthesis and Biological Evaluation
- CAR-T cell therapy research
- T-cell and B-cell Immunology
- Protein purification and stability
- Glycosylation and Glycoproteins Research
- Immunotherapy and Immune Responses
- Chemokine receptors and signaling
- Cancer therapeutics and mechanisms
- HER2/EGFR in Cancer Research
- Immune Cell Function and Interaction
- Advanced Biosensing Techniques and Applications
- Galectins and Cancer Biology
- Cell Adhesion Molecules Research
- Radiopharmaceutical Chemistry and Applications
- Chronic Lymphocytic Leukemia Research
- Phagocytosis and Immune Regulation
- Nanofabrication and Lithography Techniques
- Immunodeficiency and Autoimmune Disorders
- Viral Infectious Diseases and Gene Expression in Insects
- Cancer Immunotherapy and Biomarkers
- Immune cells in cancer
- Cancer Cells and Metastasis
- Acute Myeloid Leukemia Research
Loxo Oncology at Lilly (United States)
2024
Pfizer (United States)
2012-2021
Kaiser Permanente South San Francisco Medical Center
2014-2015
Gorgias Press (United States)
2008
Arqule (United States)
2006
Case Western Reserve University
2006
University at Buffalo, State University of New York
2005
Roswell Park Comprehensive Cancer Center
2005
The neonatal Fc receptor (FcRn) is expressed by cells of epithelial, endothelial and myeloid lineages performs multiple roles in adaptive immunity. Characterizing the FcRn/IgG interaction fundamental to designing therapeutic antibodies because IgGs with moderately increased binding affinities for FcRn exhibit superior serum half-lives efficacy. It has been hypothesized that 2 molecules bind an IgG homodimer disparate affinities, yet their affinity constants are inconsistent across...
Target-mediated clearance and high antigen load can hamper the efficacy dosage of many antibodies. We show for first time that mouse, cynomolgus, human cross-reactive, antagonistic anti-proprotein convertase substilisin kexin type 9 (PCSK9) antibodies J10 affinity-matured humanized J16 exhibit target-mediated clearance, resulting in dose-dependent pharmacokinetic profiles. These prevent degradation low density lipoprotein receptor, thus lowering serum levels LDL-cholesterol potently reducing...
4-1BB (CD137, TNFRSF9) is an inducible costimulatory receptor expressed on activated T cells. Clinical trials of two agonist antibodies, utomilumab (PF-05082566) and urelumab (BMS-663513), are ongoing in multiple cancer indications, both antibodies demonstrate distinct activities the clinic. To understand these differences, we solved structures human 4-1BB/4-1BBL complex, 4-1BBL trimer alone, bound to or urelumab. The complex displays a unique interaction between ligand when compared with...
Background T cell checkpoint immunotherapies have shown promising results in the clinic, but most patients remain non-responsive. CD47-signal regulatory protein alpha (SIRPα) myeloid blockade has early clinical activity hematologic malignancies. However, CD47 expression on peripheral blood limits αCD47 antibody selectivity and thus efficacy solid tumors. Methods To improve therapeutic window, we developed a novel affinity-tuned bispecific targeting programmed death-ligand 1 (PD-L1) to...
Abstract Mice transgenic for human Ig loci are an invaluable resource the production of Abs. However, such mice often do not yield mAbs as effectively conventional mouse mAbs. Suboptimal efficacy in delivery Abs might reflect imperfect interaction between membrane IgH chains and cellular signaling machinery. To obviate this problem, study we generated a humanized rat strain (OmniRat) carrying chimeric human/rat locus (comprising 22 VHs, all D JH segments natural configuration linked to CH...
Abstract The use of cytokines for immunotherapy shows clinical efficacy but is frequently accompanied by severe adverse events caused excessive and systemic immune activation. Here, we set out to address these challenges engineering a fusion protein single, potency-reduced, IL15 mutein PD1-specific antibody (anti-PD1-IL15m). This immunocytokine was designed deliver PD1-mediated, avidity-driven IL2/15 receptor stimulation PD1+ tumor-infiltrating lymphocytes (TIL) while minimally affecting...
Antibody-based therapeutics have experienced a rapid growth in recent years and are now utilized various modalities spanning from conventional antibodies, antibody-drug conjugates, bispecific antibodies to chimeric antigen receptor (CAR) T cells. Many next generation antibody achieve enhanced potency but often increase the risk of adverse events. Antibody scaffolds capable exhibiting inducible affinities could reduce events by enabling transient suspension activity. To demonstrate this, we...
The CXCR4-CXCL12 axis plays an important role in the chronic lymphocytic leukemia (CLL)-microenvironment interaction. Overexpression of CXCR4 has been reported different hematological malignancies including CLL. Binding pro-survival chemokine CXCL12 with its cognate receptor induces cell migration. CXCL12/CXCR4 signaling promotes survival and proliferation may contribute to tropism cells towards lymphoid tissues bone marrow. Therefore, we hypothesized that targeting IgG1 antibody,...
Human CLDN18.2 is highly expressed in a significant proportion of gastric and pancreatic adenocarcinomas, while normal tissue expression limited to the epithelium stomach. The restricted makes it potential drug target for treatment adenocarcinoma, as evidenced by efforts via naked antibody CAR-T modalities. Herein we describe CLDN18.2-targeting CD3-bispecific an conjugate characterization these therapeutic molecules efficacy preliminary toxicity studies. Anti-hCLDN18.2 ADC, diabody,...
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Soluble oligosaccharide mimetics of natural selectin ligands act as competitive inhibitors leukocyte adhesion in models inflammation. We quantified the binding simple oligosaccharides based on sialyl Lewis-X (sLeX) and complex molecules with core-2 structure to L- P-selectin, under both static fluid flow conditions. Isolated human neutrophils were employed mimic physiological valency selectins ligands. Surface plasmon resonance studies kinetics. observed following: (i) The functional group...
Abstract Staphylococcus aureus is both an important pathogen and a human commensal. To explore this ambivalent relationship between host microbe, we analysed the memory humoral response against IsdB, protein involved in iron acquisition, four healthy donors. Here show that all donors heavily biased use of two immunoglobulin heavy chain germlines generated high affinity (pM) antibodies neutralize IsdB NEAT domains, IGHV4-39 for NEAT1 IGHV1-69 NEAT2. In contrast to typical antibody/antigen...
FLT3 (FMS-like tyrosine kinase 3), expressed on the surface of acute myeloid leukemia (AML) blasts, is a promising AML target, given its role in development and progression leukemia, limited expression tissues outside hematopoietic system. Small molecule inhibitors have been developed, but despite having clinical efficacy, they are effective only subset patients associated with high risk relapse. A durable therapy that can target wider population needed. Here, we developed an anti-FLT3-CD3...
The commercial success of bispecific antibodies generally has been hindered by the complexities associated with generating appropriate molecules for both research scale and large manufacturing purposes. Bispecific IgG (BsIgG) based on two that use an identical common light chain can be combined a minimal set Fc mutations to drive heavy heterodimerization in order address these challenges. However, facile generation properties similar traditional monoclonal not demonstrated they have only...
Therapeutic antibodies are often engineered or selected to have high on-target binding affinities that can be challenging determine precisely by most biophysical methods. Here, we explore the dynamic range of kinetic exclusion assay (KinExA) exploiting interactions an anti-DKK antibody with a panel DKK antigens as model system. By tailoring KinExA each studied antigen, obtained apparent equilibrium dissociation constants (KD values) spanning six orders magnitude, from approximately 100 fM...
Abstract The restricted expression pattern of B-cell maturation antigen (BCMA) makes it an ideal tumor-associated (TAA) for the treatment myeloma. BCMA has been targeted by both CD3 bispecific antibody and antibody–drug conjugate (ADC) modalities, but a true comparison modalities yet to be performed. Here we utilized single develop characterize 2 ADC formats (cleavable noncleavable) compared activity in vitro vivo with aim generating optimal therapeutic. Antibody affinity, not epitope was...
Abstract Nectin-4 is an immunoglobulin-like antigen overexpressed in a variety of cancers including bladder, breast, NSCLC, and gastric. Normal tissues skin, salivary glands, bladder esophagus express only low to medium levels making the protein attractive target for cancer therapies. The approval enfortumab vedotin-ejfv, anti-Nectin-4 based antibody-drug conjugate (ADC) with microtubule inhibitor payload, either as single agent or combination pembrolizumab has been significant advancement...