The ADC of claim 9, wherein the hydroxylamine of structure 1 is conjugated to the unnatural amino acid.ġ1. The ADC of claim 1, wherein the linker has a structure as depicted in structure 1 before being coupled to the unnatural amino acid: wherein R is one or more drug moieties, which are optionally coupled to the hydroxylamine of structure 1 by one or more cleavage sites.ġ0. The ADC of claim 1, wherein Brentuximab is conjugated to two, four, six, or eight drug moieties.ĩ. The ADC of claim 1, wherein the linker comprises a hydroxylamine group and the unnatural amino acid comprises a formyl group ortho of a hydroxyl group in an aromatic ring, and wherein the hydroxylamine group of the linker forms an oxime with the formyl group of the unnatural amino acid after conjugation.Ĩ. The ADC of claim 1, wherein the linker is cleavable, such as by a protease like cathepsin B or wherein the linker comprises a valine-citrulline moiety.ħ. The ADC of claim 1, wherein the unnatural amino acid is a 2-substituted, 3-substituted or 4-substituted tyrosine or a tyrosine derivative substituted at the benzylic position or wherein the unnatural amino acid is 3-nitrotyrosine, 3-aminotyrosine, 3-azidotyrosine, 3-formyltyrosine, 3-acetyltyrosine, or 4-aminophenylalanine.Ħ. 4) or wherein the recognition sequence is VDSVEGEGEEEGEE (SEQ ID No. The ADC of claim 1, wherein the recognition sequence for tubulin tyrosine ligase has at least the amino acid sequence X 1X 2X 3X 4 (SEQ ID NO: 3), wherein X 1 and X 2 is any amino acid, X 3 is E, D or C and X 4 is E or wherein X 2 is G, S, A, V, or F and/or wherein X 1 is E, D, A, K, or P or wherein the recognition sequence is EGEE (SEQ ID No. The ADC of claim 1, wherein the drug moiety is selected from the group consisting of camptothecins, maytansinoids, calicheamycins, duocarmycins, tubulysins, amatoxins, dolastatins and auristatins such as monomethyl auristatin E (MMAE), pyrrolobenzodiazepine dimers, indolino-benzodiazepine dimers, radioisotopes, therapeutic proteins and peptides (or fragments thereof), nucleic acids, PROTACs, kinase inhibitors, MEK inhibitors, KSP inhibitors, and analogues or prodrugs thereof.Ĥ. The ADC of claim 1, wherein the heavy chains of Brentuximab have an amino acid sequence that comprises or consists of SEQ ID NO: 1 or have a sequence identity of at least 95% to SEQ ID NO: 1 and/or wherein the light chains of Brentuximab have an amino acid sequence that comprises or consists of SEQ ID NO: 2 or have a sequence identity of at least 95% to SEQ ID NO: 2 or wherein Brentuximab consists of heavy chains consisting of the amino acid sequence of SEQ ID NO: 1 and light chains consisting of the amino acid sequence of SEQ ID NO: 2.ģ. An antibody-drug conjugate (ADC) comprising: (a) Brentuximab, wherein Brentuximab comprises at the C-terminus of the light chains, the heavy chains or all of the heavy and light chains of the Brentuximab a recognition sequence for tubulin tyrosine ligase and a non-natural amino acid and (b) at least one drug moiety wherein a drug moiety is coupled to each of the non-natural amino acids via a linker.Ģ. The information presented would be insightful to all the manufacturers and stakeholders for the production of human insulins, insulin analogues or biosimilars, as they strive to make further progresses in therapeutic recombinant insulin development and production.1. In the face of increasing global demand for insulin product, there is a pressing need to develop a more efficient and economical production process. Pertinent examples are summarized and the practical aspects of integrating every procedure into a multimodal purification scheme are critically discussed. All the critical aspects of downstream processing, starting from proinsulin recovery from inclusion bodies, inclusion body washing, inclusion body solubilization and oxidative sulfitolysis, cyanogen bromide cleavage, buffer exchange, purification by chromatography, pH precipitation and zinc crystallization methods, proinsulin refolding, enzymatic cleavage, and formulation, are explained in this review. Here, a comprehensive review of downstream processing of recombinant human insulin/analogue production from E. The rising prevalence of diabetes worldwide is bound to escalate the demand for recombinant insulin therapeutics, and currently, the majority of recombinant insulin therapeutics are produced from E. Abstract : The Global Diabetes Compact was launched by the World Health Organization in April 2021 with one of its important goals to increase the accessibility and affordability of life-saving medicine-insulin.
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