Erik Karrer

Erik Karrer

San Francisco, California, United States
804 followers 500+ connections

About

Biotech professional with 20 years drug discovery experience. Demonstrated leadership in…

Activity

Experience

  • Character Biosciences Graphic
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    South San Francisco, CA

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    South San Francisco, CA

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    La Jolla, CA

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    Redwood City, CA

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    Redwood City, CA

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    Redwood City, CA

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    Redwood City, CA

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    Redwood City, CA

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    Redwood City, CA

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    La Jolla, CA

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    La Jolla, CA

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    Davis, CA

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    Davis, CA

Education

Publications

  • A Phase 1 Dose-Escalation Study of ASP2409, a Selective T-Cell Costimulation Inhibitor, in Stable Rheumatoid Arthritis Patients on Methotrexate Therapy

    Clinical Pharmacology in Drug Development

    ASP2409 represents a new class of CTLA4-Ig molecules with higher binding avidity and selectivity to CD86. This first-in-human study was to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of ASP2409 in stable rheumatoid arthritis patients on methotrexate therapy with a randomized, double-blind, placebo-controlled dose-escalation study design. Patients were enrolled and randomized in each of 8 dose-escalation cohorts ranging from 0.001 to 3.0 mg/kg to receive either…

    ASP2409 represents a new class of CTLA4-Ig molecules with higher binding avidity and selectivity to CD86. This first-in-human study was to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of ASP2409 in stable rheumatoid arthritis patients on methotrexate therapy with a randomized, double-blind, placebo-controlled dose-escalation study design. Patients were enrolled and randomized in each of 8 dose-escalation cohorts ranging from 0.001 to 3.0 mg/kg to receive either ASP2409 or placebo in a sequential manner. Escalation to higher dose levels occurred in the absence of dose-limiting toxicity. A total of 57 patients completed the study. ASP2409 showed nonlinear PK over the dose range of 0.01 to 3.0 mg/kg following a single intravenous administration, indicating target-mediated drug disposition. Area under the concentration-time curve (AUC) and maximum concentration (Cmax ) increased at a greater than dose-proportional rate. The half-life of ASP2409 increased dose dependently and ranged from 1.57 to 6.68 days. ASP2409 showed a dose-dependent increase in the extent and duration of CD86 receptor occupancy. There were no clinically relevant safety issues up to a single dose of 3.0 mg/kg. No maximum tolerated dose was reached. The incidence and duration of antidrug antibodies did not correlate with adverse events.

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  • ASP2408 and ASP2409, Novel CTLA4-Ig variants with CD86-selective Ligand Binding Activity and Improved Immunosuppressive Potency, Created by Directed Evolution

    Protein Engineering Design and Selection (PEDS)

    The CTLA4-Ig therapeutics abatacept and belatacept inhibit CD28-mediated T cell activation by binding CD80 (B7-1) and CD86 (B7-2) co-stimulatory ligands. Both compounds preferentially bind CD80, yet CD86 has been implicated as the dominant co-stimulatory ligand. Using directed evolution methods, novel CTLA4-Ig variants were created with selective CD86 binding affinity, a property that confers increased immunosuppressive potency and potentially improved efficacy and safety profiles. Relative to…

    The CTLA4-Ig therapeutics abatacept and belatacept inhibit CD28-mediated T cell activation by binding CD80 (B7-1) and CD86 (B7-2) co-stimulatory ligands. Both compounds preferentially bind CD80, yet CD86 has been implicated as the dominant co-stimulatory ligand. Using directed evolution methods, novel CTLA4-Ig variants were created with selective CD86 binding affinity, a property that confers increased immunosuppressive potency and potentially improved efficacy and safety profiles. Relative to abatacept (wild-type CTLA4-Ig), ASP2408 and ASP2409 have 83-fold and 220-fold enhanced binding affinity to CD86 while retaining 1.5-fold and 5.6-fold enhanced binding affinity to CD80, respectively. Improvements in CD86 binding affinity correlates with increased immunosuppressive potencyin vitroandin vivo Our results highlight the power of directed evolution methods to obtain non-intuitive protein engineering solutions and represent the first examples of CD86-selective CTLA4-Ig compounds that have entered clinical trials.

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  • Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of ASP2408, a Potent Selective T-Cell Costimulation Modulator After Single and Multiple Ascending Doses in Healthy Volunteers and RA Patients

    Clinical Pharmacology in Drug Development

    ASP2408 is a next-generation anti–cytotoxic T lymphocyte antigen-4 fusion protein engineered for improved CD86 binding affinity as a treatment for rheumatoid arthritis (RA). In 72 healthy subjects (n = 6/treatment), ASP2408 was administered as single ascending doses intravenously at 0.003 to 10.0 mg/kg or subcutaneously at 0.3 to 3.0 mg/kg. It showed decreased clearance and prolonged half-life with increasing doses, consistent with target-mediated disposition. The apparent bioavailability was…

    ASP2408 is a next-generation anti–cytotoxic T lymphocyte antigen-4 fusion protein engineered for improved CD86 binding affinity as a treatment for rheumatoid arthritis (RA). In 72 healthy subjects (n = 6/treatment), ASP2408 was administered as single ascending doses intravenously at 0.003 to 10.0 mg/kg or subcutaneously at 0.3 to 3.0 mg/kg. It showed decreased clearance and prolonged half-life with increasing doses, consistent with target-mediated disposition. The apparent bioavailability was 36.3%–56.7% across single subcutaneous doses. Sixteen RA patients (n = 8/treatment) on stable methotrexate received 3 × 3.0 mg/kg subcutaneously every 4 weeks or every 2 weeks. Similar to single-dose treatment, ASP2408 concentrations peaked 2 to 3 days postdose, with a median t1/2 of approximately 8 days. Using CD86 receptor occupancy (RO) as a mechanistic biomarker, ASP2408 demonstrated dose-dependent binding to its target. ASP2408 3.0 mg/kg subcutaneously every 4 weeks and every 2 weeks led to a mean %CD86 RO ≥ 74.7% and ≥ 81.5%, respectively, within each dosing interval. ASP2408 was well tolerated across studies with no evidence of dose-limiting toxicity or clinically significant changes in clinical laboratory test results, vital signs, or 12-lead electrocardiograms. ASP2408 elicited antidrug antibodies in the majority of patients, but with no clinical sequelae.

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  • A Pilot Trial Targeting the ICOS-ICOS-L Pathway in Nonhuman Primate Kidney Transplantation.

    American Journal of Transplantation - doi: 10.1111/ajt.13100

    Costimulation blockade with the B7-CD28 pathway-specific agent belatacept is now used in clinical kidney transplantation, but its efficacy remains imperfect. Numerous alternate costimulatory pathways have been proposed as targets to synergize with belatacept, one of which being the inducible costimulator (ICOS)-ICOS ligand (ICOS-L) pathway. Combined ICOS-ICOS-L and CD28-B7 blockade has been shown to prevent rejection in mice, but has not been studied in primates. We therefore tested a novel…

    Costimulation blockade with the B7-CD28 pathway-specific agent belatacept is now used in clinical kidney transplantation, but its efficacy remains imperfect. Numerous alternate costimulatory pathways have been proposed as targets to synergize with belatacept, one of which being the inducible costimulator (ICOS)-ICOS ligand (ICOS-L) pathway. Combined ICOS-ICOS-L and CD28-B7 blockade has been shown to prevent rejection in mice, but has not been studied in primates. We therefore tested a novel ICOS-Ig human Fc-fusion protein in a nonhuman primate (NHP) kidney transplant model alone and in combination with belatacept. ICOS-Ig did not prolong rejection-free survival as a monotherapy or in combination with belatacept. In ICOS-Ig alone treated animals, most graft-infiltrating CD4(+) and CD8(+) T cells expressed ICOS, and ICOS(+) T cells were present in peripheral blood to a lesser degree. Adding belatacept reduced the proportion of graft-infiltrating ICOS(+) T cells and virtually eliminated their presence in peripheral blood. Graft-infiltrating T cells in belatacept-resistant rejection were primarily CD8(+) CD28(-) , but importantly, very few CD8(+) CD28(-) T cells expressed ICOS. We conclude that ICOS-Ig, alone or combined with belatacept, does not prolong renal allograft survival in NHPs. This may relate to selective loss of ICOS with CD28 loss.

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  • Strategies to Develop Allergy Therapeutics with Applications of Directed Molecular Evolution

    Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents

    Karrer E, Bass S, Parmley S and Punnonen J: Strategies to Develop Allergy Therapeutics with Applications of Directed Molecular Evolution. Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents 2: 228-236 (2003).

  • Display epitopes on the surface of tobacco mosaic virus: Impact of charge and isoelectric point of the epitope on virus-host interactions

    J. Mol. Biol

    Bendahmane M, Koo M, Karrer E and Beachy RN: Display epitopes on the surface of tobacco mosaic virus: Impact of charge and isoelectric point of the epitope on virus-host interactions. J. Mol. Biol. 290: 9-20 (1999).

  • Cloning of tobacco genes that elicit the hypersensitive response

    Plant Mol. Biol.

    Karrer E, Beachy R, Holt C: Cloning of tobacco genes that elicit the hypersensitive response. Plant Mol. Biol. 36: 681-690 (1998).

  • Three cis-elements required for rice alpha-amylase Amy3D expression during sugar starvation

    Plant Mol. Biol.

    Hwang Y-S, Karrer E, Thomas BR, Chen L and Rodriguez RL: Three cis-elements required for rice alpha-amylase Amy3D expression during sugar starvation. Plant Mol. Biol. 36: 331-341 (1998)

  • In situ isolation of mRNA from individual plant cells: Creation of cell-specific cDNA libraries

    Proc. Natl. Acad. Sci.

    Karrer E, Lincoln J, Hogenhout S, Bennett A, Bostock R, Martineau B, Lucas W, Gilchirst D, and Alexander D: In situ isolation of mRNA from individual plant cells: Creation of cell-specific cDNA libraries. Proc. Natl. Acad. Sci. 92: 3814-3818 (1995).

  • Metabolic regulation of rice alpha-amylase and sucrose synthase genes in planta.

    The Plant Journal

    Karrer E, and Rodriguez R: Metabolic regulation of rice -amylase and sucrose synthase genes in planta. The Plant J. 2: 517-523 (1992).

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Patents

  • Immunosuppressive polypeptides and nucleic acids

    Issued US 8,318,176

    U.S. Patent # 8,318,176: Immunosuppressive polypeptides and nucleic acids - Karrer EE, Paidhungat MM, Bass SH, Neighbors M, Punnonen J and Chapin SJ. Issued November 27, 2012.

  • Immunosuppressive polypeptides and nucleic acids

    Issued US 8,283,447

    U.S. Patent # 8,283,447: Immunosuppressive polypeptides and nucleic acids - Karrer EE, Paidhungat MM, Bass SH, Neighbors M, Punnonen J and Chapin SJ. Issued October 9, 2012.

  • Immunosuppressive polypeptides and nucleic acids

    Issued US 8,268,587

    U.S. Patent # 8,268,587: Immunosuppressive polypeptides and nucleic acids - Karrer EE, Paidhungat MM, Bass SH, Neighbors M, Punnonen J and Chapin SJ. Issued Sept 18, 2012

  • Antibody diversity generation

    Issued US 8,252,727

    U. S. Patent # 8,252,727: Antibody diversity generation – Karrer Erik, Bass Steven H, Whalen Robert and Patten Philip A. Issued August 28, 2012

  • Immunosuppressive polypeptides and nucleic acids

    Issued US 8,071,095

    U. S. Patent # 8,071,095: Immunosuppressive polypeptides and nucleic acids - Karrer Erik E, Paidhungat MM, Bass SH, Neighbors M, Punnonen J and Chapin SJ. Issued December 6, 2011

  • Immunosuppressive Polypeptides and Nucleic Acids

    Issued US 7,794,718

    U.S. Patent # 7,794,718: Immunosuppressive Polypeptides and Nucleic Acids – Karrer EE, Paidhungat MM, Bass SH, Neighbors M, Punnonen J and Chapin SJ. Issued September 14, 2010.

  • THERAPEUTIC COMPOSITIONS AND METHODS FOR AGE-RELATED MACULAR DEGENERATION

    Filed PCT/US2023/070241

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  • THERAPEUTIC LIPID PROCESSING COMPOSITIONS AND METHODS FOR TREATING AGE-RELATED MACULAR DEGENERATION

    Filed PCT/US2023/067012

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  • Polypeptide inhibitors of VLA4

    Filed US 20120135912

    U. S. Patent Application # 20120135912: Polypeptide inhibitors of VLA4 – Paidhungat Madan M, Nanisetti Amulya, Bouquin Thomas, Andersen Kim Vilbour, Chapin Stephen J, Krebber Claus, Fan Rong A, Malashock Daniel, Brideau-Andersen Amy, Karrer Erik, Devens Bruce, Bass Stephen H. Published May 31, 2012

  • Polypeptide inhibitors of VLA4

    Filed EU EP2569331

    Paidhungat Madan M, Nanisetti Amulya, Bouquin Thomas, Andersen Kim Vilbour, Chapin Stephen J, Krebber Claus, Fan Rong A, Malashock Daniel, Brideau-Andersen Amy, Karrer Erik, Devens Bruce, Bass Stephen H

  • Immunosuppressive Polypeptides and Nucleic Acids

    Filed EU EP2385065

    European Patent Application # EP2385065: Immunosuppressive Polypeptides and Nucleic Acids - Karrer EE, Paidhungat MM, Bass SH, Neighbors M, Punnonen J and Chapin SJ. Published November 9, 2011

  • Immunosuppressive Polypeptides and Nucleic Acids

    Filed EU EP2222697

    European Patent Application # EP2222697: Immunosuppressive Polypeptides and Nucleic Acids - Karrer EE, Paidhungat MM, Bass SH, Neighbors M, Punnonen J and Chapin SJ. Published September 1, 2010

Honors & Awards

  • SVP Award for Excellence

    Astellas

    Recognizing contributions towards the successful integration of Perseid into the global Astellas organization

  • NIH National Research Service Award for Postdoctoral Fellows

    NIH

  • Letter of Distinction

    UC Davis

    Recognition of outstanding performance during Ph.D. qualifying examinations

Languages

  • German

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