Exploring the effects of linker composition on site-specifically modified antibody–drug conjugates

Albers, Aaron E.; Garofalo, Albert W.; Drake, Penelope M.; Kudirka, Romas; Hart, Gregory W. de; Barfield, Robyn M.; Baker, J. L.; Bañas, Stefanie; Rabuka, David

doi:10.1016/j.ejmech.2014.08.062

Cited by 38 publications

(31 citation statements)

References 20 publications

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“…The HIPS ligation is a quick reaction carried out at neutral pH to produce stable conjugates similar to the oxime-linked conjugate [69]. Trastuzumab with an aldehyde tag at three different sites was conjugated with five different linker HIPS-maytansinoids to produce a panel of ADCs to explore the impact of small changes in linker design on ADC potency and stability [70].…”

Section: Enzyme Modification Conjugationsmentioning

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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Section: Enzyme Modification Conjugationsmentioning

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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“…52,53 In our setup, N-termini of the dimeric molecule 1 were decorated by an aldehyde-specific model cargo 7 using oxime ligation. 31,32,54 To this end, aminooxymodified fluorescent dye TAMRA 7 (see Supplementary Section 1) reacted with 1 under mild acidic conditions towards 10 (Scheme 1).…”

Section: Internalization Of Hybrid Constructs By C-metoverexpressing mentioning

confidence: 99%

“…Thus, the Pictet-Spengler reaction 52,53,55,56 or recently reported trapped Knoevenagel condensation could become viable alternatives. 57 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 To further functionalize the Fc fragment carrying fluorescent cargo at the N-terminus (1o), we coupled PNA 2 using eSrtA-mediated ligation towards 11.…”

Section: Internalization Of Hybrid Constructs By C-metoverexpressing mentioning

confidence: 99%

Self-Assembled Hybrid Aptamer-Fc Conjugates for Targeted Delivery: A Modular Chemoenzymatic Approach

et al. 2015

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Over the past decade, DNA and RNA aptamers have attracted keen research interest due to their ability to specifically bind targets of therapeutic relevance. However, their application is often hampered by a short serum half-life and missing effector functions. Conjugation of aptamers to antibody Fc fragments could improve pharmacokinetics, enable immune effector mechanisms, and provide an option for the introduction of desired payloads (e.g., toxins or fluorescent dyes). We developed a modular scaffold-supported system based on human IgG1 Fc fragments, which allows for its dual functionalization with moieties of interest. In our approach, two bioorthogonal, enzyme-mediated reactions were used in combination with oxime ligation and self-assembly based on PNA-DNA base pairing. Thus, an engineered synthetic peptide nucleic acid (PNA) oligomer was coupled to the C-termini of the Fc dimer upon sequence-specific sortase A-mediated transpeptidation. Hybridization of the resulting Fc-PNA conjugate with a tailored DNA aptamer that binds cancer-related hepatocyte growth factor receptor (c-MET) led to a hybrid construct which showed strong and specific binding to c-MET and was readily internalized by c-MET-overexpressing cells. To install an additional orthogonally addressable site, aldehyde tag technology was applied followed by oxime ligation with an aminooxy-bearing fluorescent dye as model cargo. Delivery of fluorescent probe specifically to c-MET-overexpressing cells was confirmed by flow cytometry. Our approach can provide access to engineered aptamer-Fc conjugates with desired target specificity and cytotoxic payloads.

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“…For example, a disulphide linker with variable hindrance was tested for ado-trastuzumab emtansine, 16,46 and several conjugates were tested for the same antibody exploiting an aldehyde group. 47 Linker design and optimization is still a trial and error process, but some clear principles are falling into place. 26 At the same time, there is a pressing need for more specific analytical techniques, useful to assess the structural effect of conjugation, 48 and this becomes even more relevant on the manufacturing side of ADCs, where further issues need to be addressed (like, for example, in the case of trisulphide modification).…”

Section: Novel Linkersmentioning

confidence: 99%

Antibody–drug conjugates: targeted weapons against cancer

Iamele¹,

Vecchia²,

Scotti³

2015

ANTI

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Antibody-drug conjugates (ADCs) are formed by a targeting antibody conjugated to a chemotherapeutic molecule through a linker. Recent data demonstrate that ADCs represent a valuable advancement for the clinics and, despite their recent appearance in medicine, they are already undergoing an innovation wave aimed at targeting all three ADC building blocks. Thus, new antibody formats are being engineered, site-specific linkers are being designed, and highly toxic molecules, like RNA polymerase inhibitors, are starting to be used for conjugation. These molecules were previously considered extremely toxic and could not be used as chemotherapeutic drugs. In this review, we will present an overview of current cancer treatments and their limitations, and the logic that has led to the generation of ADCs. Their mechanism of action will be outlined, and the most recent novelties in linker design and optimization will be discussed, along with present and near future discoveries in the current ADC research pipeline.

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Exploring the effects of linker composition on site-specifically modified antibody–drug conjugates

Cited by 38 publications

References 20 publications

Emerging formats for next-generation antibody drug conjugates

Emerging formats for next-generation antibody drug conjugates

Self-Assembled Hybrid Aptamer-Fc Conjugates for Targeted Delivery: A Modular Chemoenzymatic Approach

Antibody–drug conjugates: targeted weapons against cancer

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Exploring the effects of linker composition on site-specifically modified antibody–drug conjugates

Cited by 38 publications

References 20 publications

Emerging formats for next-generation antibody drug conjugates

Emerging formats for next-generation antibody drug conjugates

Self-Assembled Hybrid Aptamer-Fc Conjugates for Targeted Delivery: A Modular Chemoenzymatic Approach

Antibody&ndash;drug conjugates: targeted weapons against cancer

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Antibody–drug conjugates: targeted weapons against cancer