Immunology and Biotherapies

Roche currently has several different therapeutic antibody technologies in early clinical development which in the future could hopefully be a strong pillar in addressing the complexity of targeting more than 250 cancer diseases.

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

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

Antibody–drug conjugates: targeted weapons against cancer Luisa Iamele, Luca Vecchia, Claudia ScottiDepartment of Molecular Medicine, Unit of Immunology and General Pathology, University of Pavia, Pavia, PV, Italy All authors contributed equally...

Via Krishan Maggon

PolyTherics has developed its range of novel ThioBridge™ linkers to efficiently conjugate drugs to antibodies to create less heterogeneous ADCs with better stability. Our proprietary technology uses site-specific conjugation to naturally occurring inter-chain disulfides avoiding the need for antibody re-engineering to create a site of attachment.

We offer a range of cytotoxic payloads with different mechanisms of action which we can conjugate to your antibody using our ThioBridge™ technology. These payloads have been developed internally or are accessed through our partnerships.

PolyTherics can undertake the conjugation and analytical characterisation of the ADC in its own laboratories or provide a ThioBridge™ precursor reagent to you to use in-house. In addition to producing ADCs for potential therapeutic use, we can also produce antibody-conjugates for diagnostic & imaging purposes and ADCs using standard conjugation technologies for comparative purposes.

 

Optimisation of pharmacokineticsPolyTherics provides a range of site-specific conjugation technologies to optimise the pharmacokinetics (PK) and pharmacodynamics (PD) of therapeutic peptides and proteins, including antibody fragments and other protein scaffolds, by extending their half-life to reduce the frequency of dosing. This improves patient compliance and can reduce the cost of treatment. PolyTherics also provides a low viscosity polymer, PolyPEG™, to enable the easier injection of conjugated proteins which need to be administered at high concentration. 

Our proprietary PEGylation technologies enable polyethylene glycol (PEG) or other polymers to be attached to different specified sites depending on the nature of the protein. TheraPEG™ conjugates PEG at disulfide bonds, HiPEG™ conjugates PEG to poly-histidine motifs and CyPEG™ conjugates PEG to a thiol on a free cysteine. These technologies are used to conjugate both linear and branched PEG to therapeutic proteins and can be used for PolyPEG™ conjugation.

The conjugation processes are efficient, helping keep the cost of manufacture down, and the conjugated products are more stable and homogeneous than can be achieved with other well-established conjugation technologies.

We can PEGylate your protein or peptide in our laboratories or provide you with our conjugation reagents so you can undertake the work yourself. Our reagents are available in a range of PEG molecular weights and formats, including linear and branched PEGs.

Via Krishan Maggon