Immunology and Biotherapies

Abstract

The concept of using immunotherapy to treat melanoma has existed for decades. The rationale comes from the knowledge that many patients with melanoma have endogenous immune responses against their tumor cells and clinically meaningful tumor regression can be achieved in a minority of patients using cytokines such as interleukin-2 and adoptive cellular therapy. In the last 5 years there has been a revolution in the clinical management of melanoma in large measure based on the development of antibodies that influence T cell regulatory pathways by overcoming checkpoint inhibition and providing co-stimulation, either of which results in significantly more effective immune-mediated tumor destruction. This review will describe the pre-clinical and clinical application of antagonistic antibodies targeting the T-cell checkpoints cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1), and agonistic antibodies targeting the costimulatory pathways OX40 and 4-1BB. Recent progress and opportunities for future investigation of combination antibody therapy will be described.

Via Krishan Maggon

Highlights

 

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Engineering of smaller antibody scaffolds can overcome the limitations of full-size antibodies.

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This review focuses on engineered IgG1 Fc based antibody fragments and domains as novel scaffolds.

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The Fc based binders are promising candidate therapeutics with small size and long half-lives.

 

Abstract

Therapeutic monoclonal antibodies (mAbs) have been successful for the therapy of a number of diseases mostly cancer and immune disorders. However, the vast majority of mAbs approved for clinical use are full size, typically in IgG1 format. These mAbs may exhibit relatively poor tissue penetration and restricted epitope access due to their large size. A promising solution to this fundamental limitation is the engineering of smaller scaffolds based on the IgG1 Fc region. These scaffolds can be used for the generation of libraries of mutants from which high-affinity binders can be selected. Comprised of the CH2 and CH3 domains, the Fc region is important not only for the antibody effector function but also for its long half-life. This review focuses on engineered Fc based antibody fragments and domains including native (dimeric) Fc and monomeric Fc as well as CH2 and monomeric CH3, and their use as novel scaffolds and binders. The Fc based binders are promising candidate therapeutics with optimized half-life, enhanced tissue penetration and access to sterically restricted binding sites resulting in an increased therapeutic efficacy. This article is part of a Special Issue entitled: Recent advances in molecular engineering of antibody.

Via Krishan Maggon

Abstract

Bispecific antibodies are on the cusp of coming of age as therapeutics more than half a century after they were first described. Two bispecific antibodies, catumaxomab (Removab®, anti-EpCAM × anti-CD3) and blinatumomab (Blincyto®, anti-CD19 × anti-CD3) are approved for therapy, and >30 additional bispecific antibodies are currently in clinical development. Many of these investigational bispecific antibody drugs are designed to retarget T cells to kill tumor cells, whereas most others are intended to interact with two different disease mediators such as cell surface receptors, soluble ligands and other proteins. The modular architecture of antibodies has been exploited to create more than 60 different bispecific antibody formats. These formats vary in many ways including their molecular weight, number of antigen-binding sites, spatial relationship between different binding sites, valency for each antigen, ability to support secondary immune functions and pharmacokinetic half-life. These diverse formats provide great opportunity to tailor the design of bispecific antibodies to match the proposed mechanisms of action and the intended clinical application.

Via Krishan Maggon