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FDA approves first radiopharmaceutical 'peptide-drug conjugate' somatostatin-based OctreoScan for imaging (1994) and LUTATHERA for therapy (2018) of neuroendocrine tumors

LUTATHERA is a conjugate comprised of Octreotate, a peptide derived from the neurotransmitter somatostatin, and the chelating agent DOTA complexed with the radioactive isotope 77Lu.  The peptide-isotope conjugate was approved by U. S. FDA to treat neuroendocrine tumors.

Side effects continue to undermine the well-being of cancer patients undergoing therapy.  To reduce side effects associated with current therapeutics, antibodies have been utilized as the delivery vector for previously isolated cytotoxic drugs.  The ability of the antibodies to bind to molecules expressed on the surface of tumor cells provided a means to deliver drugs selectively to tumor cells.  Using special linkers (cleavable or non-cleavable type), various cytotoxic drugs have been conjugated to 'tumor-specific antibodies'.  To date, U. S. FDA has approved ca. 11 such antibody-drug conjugates.  These include Enhertu (anti-Her2 antibody linked topoisomerase I inhibitor; AstraZeneca-Daiichi Sankyo) for urothelial cancer, Kadcyla (anti-Her2 antibody linked to antimicrotubule drug; Genentech-Roche) for metastatic breast cancer, Lumoxiti (anti-CD22 antibody linked to the bacterial toxin; AstraZeneca) for relapsed hairy cell leukemia, etc.

Nevertheless, the resultant antibody-drug conjugates continued to exhibit side effects.  In the case of Enhertu, side effects include nausea, diarrhea, anemia, decreased clotting, etc.  Kadcyla is associated with thrombocytopenia (low platelet count), hepatotoxicity, heart damage, neuropathy, etc.  Several of these symptoms also occurred following the Lumoxiti treatment--i.e. in addition to the swelling of limbs, hypotension, breathing difficulty, abnormal red blood cell destruction, etc.

 To explain the off-target effects of antibody-drug conjugates, potential uptake of monoclonal antibodies lacking terminal galactose on the Fc domain by mannose receptors expressed in various immune cell types, leading to their depletion, has been suggested (Gorovits et al., 2012).   Further, the binding of antibodies to reticuloendothelial system may cause toxicity to the liver, bone marrow, and spleen.   Other limitations of using antibodies include failure to reach the brain through blood -brain barrier, poor penetration of solid tumors due to high molecular weight (~160 kD), and premature release of drugs while in circulation.  The difficulty of their preparation along with the exorbitant cost for large-scale production represents other disadvantages (Le Joncour et al., 2017).

 To address these shortcomings, peptides are increasingly being tapped for targeted drug delivery.  Peptides (as short as 7 to 12 mer) can adopt myriad conformations by altering their sequences.  Previously, these properties have been exploited to isolate 'homing peptides' (Joliot et al.., 2004).    Due to their minuscule molecular weight (1 to 2 kD), peptides allow deeper penetration into tissues--as has been demonstrated for solid tumors (Hong et al., 2000).  Additionally, peptide-conjugated drugs exhibit excellent tolerability, lesser immunogenicity, are easier to produce in large quantities, simpler purification scheme, etc.  Plus, developing peptide-drug conjugate using previously FDA-approved drugs is far less costly than discovering novel drugs, and the conjugation process is generally less complex and rapid (Vrettos et al., 2018).  


During the last several decades, significant efforts have been made by the biopharmaceutical industries to improve their application.  First, to isolate 'homing peptides', bacteriophage-based random peptide-display technology has been used extensively.  The externally displayed random peptides as part of the coat protein of M13 bacteriophages served as the main 'work horse' to isolate peptides targeting various tumors or normal tissues (Brown, 2010).  Others peptides have been derived from naturally occurring sources like the neurotransmitters (ex. octreotide) or matrix proteins (ex. RGD).  These include peptides targeting cancer cells directly (ex. LyP-1, HN-1, TGN peptide), tumor-associated vasculature (ex. RGD, NGR), tumor-associated macrophages, tumor lymphatics, etc. (Arap et al., 1998; Gray et al., 2014).  For other types of disorders, peptides that target various normal tissues (ex. immune cells, cardiac cells (ex. CTP peptide), muscle cells, kidney cells, liver cells) have been isolated (Gray et al., 2014).  The majority of previously isolated peptides bind to cell surface molecules albeit a minority retains the potential to internalize.

 Second, peptides have been engineered to improve their pharmacokinetic (traffic) or pharmacodynamic (mechanism) properties.  To increase binding affinity, peptides may be cyclized via 'stapling' (to lock their secondary structures into desired conformations).  To increase half-life, the N- or C-terminus may be chemically modified (to avoid degradation by exoproteases).   Further, specific amino acids may be replaced with D-configuration (potentially alternate residues) or unnatural amino acids (Le Joncour et al., 2018).  To avoid renal clearance, higher molecular weight entities such as PEG, fatty acid, branched amylopectin, polysialic acid, hydroxyethyl starch, etc. may be linked.  To improve oral bioavailability, it may be coated with the acid-stable coating (ex. citric acid) in the stomach, which breaks apart when it reaches higher pH of the intestine (Cooper et al., 2020).  Nevertheless, some of these modifications may run the risk of attenuating/losing the binding properties.

 Third, to conjugate peptides to drugs, both the cleavable and non-cleavable types of the linker are available (Hoppenz et al., 2020).  The cleavable types include disulfide (S-S) linkers that become cleaved upon reduction by glutathione intracellularly, pH-sensitive linkers (ex. hydrazine, acetals, imines) that are hydrolyzed at acidic pH in endosomes, etc.  Cleavable linkers also include peptides that are cleaved by matrix-metalloproteinases (MMPs) extracellularly and others (ex. Valine-Alanine or Valine-Citrulline) that are cleaved by cathepsin B inside the endosome (albeit the latter becomes cleaved in the mouse plasma) (Cooper et al., 2021).  Commonly used linkers containing 'enzyme hydrolyzable unit' may consist of carboxylic ester or an amide bond (Vrettos et al., 2018).  The 'self-immolative' (self-destructive) linker PABC (para-amino benzyl alcohol) can be used to connect peptide with drug as it could be cleaved at the enzyme hydrolyzable unit to release the peptide, and then undergo 1,6-elimination to release the unmodified drug.  Alternatively, aryl sulfate linkers that undergo 1,6-elimination to release unmodified drugs have been utilized.  The non-cleavable type, which is more stable in circulation, may be used when the peptide is intended to undergo degradation upon internalization, releasing the drug-linker complex into the cytosol.

 Recently, U. S. FDA issued the first approval of the peptide-drug conjugate to treat gastroenteropancreatic neuroendocrine tumors.  Somatostatin is a neurotransmitter and there are 5 subtypes of somatostatin receptors (SSTR); among them, SSTR2 and SSTR5 are highly expressed in neuroendocrine tumors.  Neuroendocrine tumors are derived from neuroendocrine cells and may occur in various tissue types.  Somatostatin analogs have been used as probes to image tumors in the 1980s-1990s.  Octreotide labeled with radioisotope 111In (gamma emitter; Octreoscan, Mallinckrodt) was useful for tumor imaging (albeit less effective in therapy), and was FDA approved for imaging in 1994 (ex. for PET scan with positron emitting isotope or SPECT with gamma ray emitter).  Subsequently, the FDA approved (in 2018) LUTATHERA (77Lu-DOTA-octreotate; Novartis), representing 77Lu (beta emitter) conjugated to Octreotate using the bi-functional chelating agent DOTA, was able to achieve longer progression-free survival with a higher therapeutic response rate in advanced midgut neuroendocrine tumors (Hennrich et al., 2019).


The key to preventing epidemic is the ability to diagnose the infected early to preempt further propagation.  For this, Bio-Synthesis, Inc. provides primers and probes (as well as synthetic RNA control) for COVID-19 diagnosis via RT-PCR assay.  It specializes in oligonucleotide modification and provides an extensive array of chemically modified nucleoside analogues (over ~200) including bridged nucleic acid (BNA) in addition to mRNA synthesis.  A number of options are available to label oligonucleotides (DNA or RNA) with fluorophores either terminally or internally as well as to conjugate to peptides or antibodies. It provides custom conjugation of small molecules such as chemical drugs, metabolites and labeled compounds with synthetic or natural polymers (enzymes, peptide, protein, oligonucleotide, antibody, dendrimer, nanoparticle, etc).  It recently acquired a license from BNA Inc. of Osaka, Japan, for the manufacturing and distribution of BNANC, a third generation of BNA oligonucleotides.  To meet the demands of therapeutic application, its oligonucleotide products are approaching GMP grade.  It has recently entered into collaborative agreement with Bind Therapeutics, Inc. to synthesize miR-21 blocker using BNA for triple negative breast cancer.  The BNA technology provides superior, unequalled advantages in base stacking, binding affinity, aqueous solubility and nuclease resistance.  It also improves the formation of duplexes and triplexes by reducing the repulsion between the negatively charged phosphates of the oligonucleotide backbone.  Its single-mismatch discriminating power is especially useful for diagnosis (ex. FISH using DNA probe).  For clinical application, BNA oligonucleotide exhibits lesser toxicity than other modified nucleotides.!



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