Engineered Fc based antibody domains and fragments as novel scaffolds

Ying, Tianlei; Gong, Rui; Ju, Tina W.; Prabakaran, Ponraj; Dimitrov, Dimiter S.

doi:10.1016/j.bbapap.2014.04.018

Cited by 37 publications

(27 citation statements)

References 49 publications

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“…Indeed, a number of anti-FcgRI immunotoxins, composed of anti-FcgRI antibodies attached to various toxins, have recently been developed, and their efficacy has been demonstrated in vitro and in mouse models of different diseases, such as chronic cutaneous inflammation, rheumatoid arthritis, acute myeloid leukemia. 11,12,25,26,36,37 In this regard, the use of mFc to deliver therapeutic molecules could be particularly valuable because it provides extended circulating half-life and improved biodistribution by interacting with FcRn, 38,39 and it offers additional targeting to FcgRI-overexpressed cells, which in certain cases could lead to greater therapeutic benefit. For instance, one immediate application is to fuse mFc with anti-FcgRI immunotoxins.…”

Section: Discussionmentioning

confidence: 99%

Monomeric IgG1 Fc molecules displaying unique Fc receptor interactions that are exploitable to treat inflammation-mediated diseases

Ying¹,

Yang

Wang

et al. 2014

mAbs

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The IgG1 Fc is a dimeric protein that mediates important antibody effector functions by interacting with Fcg receptors (FcgRs) and the neonatal Fc receptor (FcRn). Here, we report the discovery of a monomeric IgG1 Fc (mFc) that bound to FcgRI with very high affinity, but not to FcgRIIIa, in contrast to wild-type (dimeric) Fc. The binding of mFc to FcRn was the same as that of dimeric Fc. To test whether the high-affinity binding to FcgRI can be used for targeting of toxins, a fusion protein of mFc with a 38 kDa Pseudomonas exotoxin A fragment (PE38), was generated. This fusion protein killed FcgRI-positive macrophage-like U937 cells but not FcgRI-negative cells, and mFc or PE38 alone had no killing activity. The lack of binding to FcgRIIIa resulted in the absence of Fc-mediated cytotoxicity of a scFv-mFc fusion protein targeting mesothelin. The pharmacokinetics of mFc in mice was very similar to that of dimeric Fc. The mFc's unique FcgRs binding pattern and related functionality, combined with its small size, monovalency and the preservation of FcRn binding which results in relatively long half-life in vivo, suggests that mFc has great potential as a component of therapeutics targeting inflammation mediated by activated macrophages overexpressing FcgRI and related diseases, including cancer. Significance StatementFc fusions are a well-established class of therapeutics, but their uses have been limited by several factors, such as the relatively large size and unwanted cytotoxic effects. Here, we describe a small monomeric Fc that can be exploited to greatly expand the Fc-related therapeutic applications, owing to its unique receptor binding pattern and related functionality. The mFc 1) binds to FcRn and exhibits a similar in vivo half-life to that of dimeric Fc; 2) lacks binding to FcgRIIIa which results in the absence of Fcmediated cytotoxicity; 3) possesses high-affinity binding to FcgRI and can be used for FcgRI targeting. The mFc thus has potential as a component of therapeutics targeting inflammation mediated by activated macrophages overexpressing FcgRI.

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Section: Discussionmentioning

confidence: 99%

Monomeric IgG1 Fc molecules displaying unique Fc receptor interactions that are exploitable to treat inflammation-mediated diseases

Ying¹,

Yang

Wang

et al. 2014

mAbs

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“…In collaboration with Heidelberg Pharma, they are exploring the use of this format for smaller ADCs using standard lysine chemistry in a HER2 model [106]. Fc-based binding fragments based on other technologies are emerging [107].…”

Section: Retaining the Fc Alonementioning

confidence: 99%

Emerging formats for next-generation antibody drug conjugates

Deonarain¹,

Yahioglu²,

Stamati³

et al. 2015

Expert Opinion on Drug Discovery

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“…We devised a novel strategy to engineer FcRn binding into small-size antibody domains to explore whether their enhanced FcRn binding would correlate with prolonged in vivo half-life. [30][31][32] Our strategy used a combination of in silico and screening-based rational design to overcome the 2 limitations described above. Using molecular dynamics simulations, we found that CH2-CH3 hybrid structures with 8-mer peptide linkers between m01s and the CH3 FcRn-binding motif superimposed with the structure of Fc, and that a proline residue following the linker improved the backbone rigidity of the CH3 motif.…”

Section: Discussionmentioning

confidence: 99%

Engineered antibody domains with significantly increased transcytosis and half-life in macaques mediated by FcRn

Ying¹,

Wang

Yang

et al. 2015

mAbs

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(2015) Engineered antibody domains with significantly increased transcytosis and half-life in macaques mediated by FcRn, mAbs, 7:5, 922-930, DOI: 10.1080/19420862.2015 Engineered antibody domains (eAds) are promising candidate therapeutics but their half-life is relatively short partly due to weak or absent binding to the neonatal Fc receptor (FcRn). We developed a novel approach to increase the eAd binding to FcRn based on a combination of structure-based design, computational modeling and phage display methodologies. By using this approach, we identified 2 IgG1 CH2-derived eAds fused to a short FcRn-binding motif derived from IgG1 CH3 that exhibited greatly enhanced FcRn binding with strict pH dependency. Importantly, the increased affinity resulted in significantly enhanced FcRn-mediated epithelial transcytosis and prolonged elimination half-life (mean 44.1 hours) in cynomolgus macaques. These results demonstrate for the first time that the half-life of isolated eAds can be prolonged (optimized) by increasing their binding to FcRn while maintaining their small size, which has important implications for development of therapeutics, including eAd-drug conjugates with enhanced penetration in solid tissues.

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Engineered Fc based antibody domains and fragments as novel scaffolds

Cited by 37 publications

References 49 publications

Monomeric IgG1 Fc molecules displaying unique Fc receptor interactions that are exploitable to treat inflammation-mediated diseases

Monomeric IgG1 Fc molecules displaying unique Fc receptor interactions that are exploitable to treat inflammation-mediated diseases

Emerging formats for next-generation antibody drug conjugates

Engineered antibody domains with significantly increased transcytosis and half-life in macaques mediated by FcRn

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