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• W3101183925 abstract "Background Antibody-drug conjugates (ADC) increase the efficacy of current chemotherapeutics, decrease off site toxicity, and pair drug function with immunomodulatory effects. Current ADC platforms depend on the use of covalent linker molecules between the antibody and the drug of choice. This approach leads to significant variation in the number of drug molecules bound, the location of their binding, and inconsistency in maintaining the structure and antigen affinity of the antibody. Because of this, covalent-based ADC development requires extensive separation steps to isolate the ideal isotypes of the ADC. This testing and separation must be repeated for each antibody and each drug considered. Here we present a peptide that non-covalently binds multiple clinically relevant IgG1 antibodies at a controlled ratio and location, then demonstrate its use as a modular ADC linker platform. Methods Peptide-antibody and antibody-antigen affinity were determined using Biacore surface plasmon resonance. Peptides conjugated with alexafluor or DM1 were purified using HPLC and structure was confirmed through mass spectrometry. Flow cytometry verified delivery of peptide-atezolizumab conjugates to C1861 PDL1+ melanoma cells. Peptide-DM1 potency was determined in-vitro using a calcein-AM and propridium iodine live/dead cell double staining. Results Antibody-Binding Peptide Linker (APL) was developed from a series of space filling amino acid substitutions at key residues on an 18-mer peptide derived from a hydrophobic pocket on human albumin (figure 1a). A lysine containing tail was added to the C-terminus for conjugation to small molecule therapeutics through amine coupling. APL has nanomolar binding affinity for the fab region of IgG1 antibodies including rituximab (KD= 1.85 × 10 -8 ), bevacizumab (KD= 5.2 × 10 -8 ), trastuzumab (KD= 8.87 × 10 -8 ), and atezolizumab (KD= 3.78 × 10 -8 ) (figure 1b). Kinetic binding models, performed by Biacore surface plasmon resonance, showed a 2:1 association of peptide to antibody. All four antibodies retained their antigen affinity when bound by APL (figure 2a). Labeling of APL with an alexafluor showed delivery to PDL1+ melanoma cells when given bound to the anti-PDL1 antibody atezolizumab (figure 2b). Conjugation of APL with the tubulin inhibitor DM1 (figure 2c) resulted in a drug conjugated peptide that retained the potency of the drug itself (figure 2d). Abstract 616 Figure 1 a) APLinker peptide structure showing the hydrophobic side chains necessary for antibody binding (green), an isoleucine substitution to increase affinity (red), and the addition of a lysine residue to the C terminus for amine conjugation. b) Binding affinity of each peptide mutant to common therapeutic antibodies, determined using Biacore surface plasmon resonance Abstract 616 Figure 2 a) Affinity of clinical antibodies for their antigen when bound by APLinker peptide at different molar ratios. b) Labeling of PDL1+ C8161 melanoma cells with atezolizumab bound by AF647 conjugated APLinker. c) Structure of APLinker conjugated with the chemotherapeutic DM1 onto the C-terminus lysine using an SMCC crosslinker. d) In-vitro proliferation assay of DM1 alone and APL-DM1 conjugate using A-375 melanoma cells. Conclusions Antibody-Binding Peptide Linker (APL) non-covalently binds clinical IgG1 antibodies at a fixed two to one ratio without affecting antigen affinity. Conjugation of APL with a drug of choice provides a modular Antibody-Drug Conjugate platform where both the antibody and drug can be substituted with ease." @default.
• W3101183925 created "2020-11-23" @default.
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• W3101183925 date "2020-11-01" @default.
• W3101183925 modified "2023-09-27" @default.
• W3101183925 title "616 A novel non-covalent linker peptide with nanomolar affinity for clinical IgG1 antibodies preserves antibody-antigen affinity and drug potency against PDL1+ melanoma when conjugated with DM1" @default.
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• W3101183925 doi "https://doi.org/10.1136/jitc-2020-sitc2020.0616" @default.
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