Tailoring Natural Effector Functions: Antibody Engineering Beyond Humanization

Brekke, Ole Henrik; Thommesen, John Einar

doi:10.1385/1-59259-334-8:383

Cited by 4 publications

(3 citation statements)

References 22 publications

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“…Interactions with the FcRN receptor were not altered in LY2189265 to preserve extended time-action. The IgG4 isotype, our choice for LY2189265, has been shown to be unable to activate complement, the first step in antibody-dependent complement-mediated cell lysis [21].…”

Section: Discussionmentioning

confidence: 99%

Engineering and characterization of the long‐acting glucagon‐like peptide‐1 analogue LY2189265, an Fc fusion protein

Glaesner

Vick

Millican

et al. 2010

Diabetes Metabolism Res

244

199

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Background Glucagon-like peptide-1 (GLP-1) receptor agonists are novel agents for type 2 diabetes treatment, offering glucose-dependent insulinotropic effects, reduced glucagonemia and a neutral bodyweight or weight-reducing profile. However, a short half-life (minutes), secondary to rapid inactivation by dipeptidyl peptidase-IV (DPP-IV) and excretion, limits the therapeutic potential of the native GLP-1 hormone. Recently, the GLP-1 receptor agonist exenatide injected subcutaneously twice daily established a novel therapy class. Developing long-acting and efficacious GLP-1 analogues represents a pivotal research goal. We developed a GLP-1 immunoglobulin G (IgG4) Fc fusion protein (LY2189265) with extended pharmacokinetics and activity.

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Section: Discussionmentioning

confidence: 99%

Engineering and characterization of the long‐acting glucagon‐like peptide‐1 analogue LY2189265, an Fc fusion protein

Glaesner

Vick

Millican

et al. 2010

Diabetes Metabolism Res

244

199

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“…GLP-1R antagonism via targeted antibodies such as TB-001-003 and TB-222-023 offer great potential in this regard because they demonstrate a much longer half-life, which would require less frequent dosing and, therefore, ease of treatment for patients. Antibody therapeutics have many advantages over peptides, and antibodies can be engineered to avoid toxic effector functions, including antibody-dependent cellular cytotoxicity ( 41 ). Antibodies are processed through intracellular recycling ( 42 ), and antibody half-life can be enhanced through engineering of the crystallizable fragment region ( 43 ).…”

Section: Discussionmentioning

confidence: 99%

Optimization of a Glucagon-Like Peptide 1 Receptor Antagonist Antibody for Treatment of Hyperinsulinism

Peterson,

Juliana,

et al. 2023

Diabetes

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Congenital hyperinsulinism (HI) is a genetic disorder in which pancreatic beta cell insulin secretion is excessive and results in hypoglycemia that can cause brain damage or death without treatment. Most patients with loss-of-function mutations in ABCC8 and KCNJ11, the genes encoding the beta cell ATP sensitive potassium channel (KATP), are unresponsive to diazoxide, the only FDA approved medical therapy, and require a pancreatectomy. The glucagon-like peptide 1 receptor (GLP-1R) antagonist exendin-(9-39) is an effective therapeutic agent to inhibit insulin secretion in both congenital and acquired hyperinsulinism. Previously, we identified a highly potent antagonist antibody, TB-001-003, which was derived from our synthetic antibody libraries that were designed to target G protein-coupled receptors. Here, we designed a combinatorial variant antibody library to optimize the activity of TB-001-003 against GLP-1R and performed phage-display on cells overexpressing GLP-1R. One antagonist, TB-222-023, is more potent than exendin-(9-39), also known as Avexitide. TB-222-023 effectively decreased insulin secretion in primary isolated pancreatic islets from a mouse model of hyperinsulinism, Sur1-/- mice, and in islets from an infant with HI as well as increased plasma glucose and decreased the insulin to glucose ratio in Sur1-/- mice. These findings demonstrate that targeting GLP-1R with an antibody antagonist is an effective and innovative strategy for treatment of hyperinsulinism.

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“…17 IgG1 Fc has generally been used as a conjugate to prolong the half-life of a bioactive molecule, but has its shortcomings, such as complement-dependent and antibodydependent cell-mediated cytotoxicity. 28 When compared together, there is a 10-fold difference in the ability of IgG1 and IgG4 to bind to Fcg RI (CD64, high-affinity Fc receptor). 29 Therefore, we replaced IgG1 with a variant IgG4, containing 3 amino acid substitutions relative to native IgG4 Fc (S228P, F234A, and L235A) and deleted the C-terminal lysine of the IgG4 Fc to lower the immunogenicity and stabilize the IgG4 peptide.…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo characterization of a novel long-acting GLP-1 receptor agonist, exendin-4–Fc fusion protein

Wang

et al. 2017

RSC Adv.

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Tailoring Natural Effector Functions: Antibody Engineering Beyond Humanization

Cited by 4 publications

References 22 publications

Engineering and characterization of the long‐acting glucagon‐like peptide‐1 analogue LY2189265, an Fc fusion protein

Engineering and characterization of the long‐acting glucagon‐like peptide‐1 analogue LY2189265, an Fc fusion protein

Optimization of a Glucagon-Like Peptide 1 Receptor Antagonist Antibody for Treatment of Hyperinsulinism

In vitro and in vivo characterization of a novel long-acting GLP-1 receptor agonist, exendin-4–Fc fusion protein

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