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Peptide-drug conjugates being developed to address the side effects issue of FDA-approved antibody-drug conjugates for cancer therapy

pHLIP is a peptide that undergoes conformational change in the acidic milieu to translocate across cell membrane of cancer cells.   A conjugate comprised of pHLIP and topoisomerase I inhibitor was developed to resolve the side effects problem associated with previously developed antibody drug conjugates that have been approved by U. S. FDA.

Considerable gains have been made in prolonging the survival of breast cancer patients over the last several decades.
  Treatment regimens comprised of anti-hormone therapy targeting the estrogen receptor pathway have provided a critical intervention strategy for estrogen receptor (ER)-positive breast cancers.  For those with Her2-positive breast cancer, the introduction of anti-Her2 antibody that blocks oncogenic signaling slowed their progression considerably.  Despite these achievements, the onset of recurrent cancers remains largely unresolved.

Most recurrent cancers are detected within 5 years of initial diagnosis.  However, recurrent cancer has been documented even after 50 years, ex. renal cell carcinoma (kidney cancer) (Walter et al., 1960).  For breast cancer, 'local recurrence' refers to cancers that have returned to the same organ after the treatment.  'Regional recurrence' refers to cancers that have relapsed at a nearby location (i.e. near neck, armpit, collar bone) containing lymph nodes (as tumor cells may spread via lymphatic vessels).  'Distal recurrence' refers to cancers that have metastasized to distinct organs (ex. bone, lung, liver, brain).

 An initial insight into the existence of "dormant" cancer cells came from transplantation studies.  Certain recipients of organ transplants subsequently developed tumors (~160 out of 1,000,000 organ transplant cases).  Subsequently, it was found that the dormant tumor cells were inadvertently transferred when the transplanted organs came from donors with a history of malignancy (Friberg et al. 2015).  Using the radio-graphically determined volumes of primary and secondary cancers of the same tumor at different time intervals, the growth rate of malignant tumors was calculated (in ~2,000 patients).  The results suggested that >75% of human malignant tumors (ex. breast cancer) may have already metastasized at the time of primary tumor diagnosis (Friberg et al. 2015; Pedersen et al., 2022).  The persistence of dormant cells is supported by the ability to detect circulating tumor cells (CTCs) even decades after the treatment (of primary tumor) (Meng et al., 2004).


Approximately ~30% (ranges from 10 to 40%) of those diagnosed with breast cancer are expected to develop metastasis, with ~90% succumbing to recurrent cancer eventually (Pedersen et al., 2021).  Among the currently used chemotherapeutics to treat metastatic breast cancer are antimicrotubule drugs (ex Taxol) or topoisomerase inhibitors.  However, the use of either drug is associated with severe side effects.  To lessen toxicity, several drugs have been conjugated to tumor-targeting antibodies for selective delivery.

 Several antibody-drug conjugates (ADC) have been approved by FDA for cancer treatment.   Trastuzumab emtansine (T-DM1 by Genentech/Roche) consists of maytansine attached to Her2-recognizing monoclonal antibody.  Sacituzumab govitecan (Trodelvy by Immunomedics) represents SN-38 (inhibits topoisomerase I) linked to monoclonal antibody targeting Trop-2 (tumor-associated calcium signal transducer 2).  Trastuzumab deruxtecan (Enhertu by Daichi Sankyo/AstraZeneca) is comprised of deruxtecan (topoisomerase I inhibitor) conjugated to anti-Her2 antibody (Herceptin).  Despite being guided by antibodies, side effects remain a critical issue for these ADCs.

 As a result, there has been an increasing pharmaceutical attempt to develop peptide-drug conjugates.  A recent report by the investigators at the Yale University School of Medicine (USA) describes the delivery of topoisomerase inhibitors using a peptide (Gayle et al., 2021).  Exatecan, an analogue of camptothecin, is an inhibitor of the topoisomerase I enzyme.  In cancer cells, the preferred processing of glucose via 'anaerobic glycolysis' than via citric acid cycle, i.e. Warburg effect (Nobel prize, 1931), leads to the production of lactic acid (due to conversion of pyruvate by lactate dehydrogenase).  The accumulation of lactic acids confers an acidic milieu to the tumor cell surface (pH 6.0-6.5) and tumor cell microenvironment (pH 6.7-7.1). The pHLIP ('pH-Low Insertion Peptide': AEQNPIYWARYADWLFTTPLLLLDLALLVDADEGT) peptide adopts an alpha helix conformation at low pH for 'directional' insertion across the cell membrane to translocate a C-terminally (the inserting end) conjugated drug into the cytosol (Wyatt et al., 2018).  Exatecan was conjugated to pHLIP (called 'CBX-12') using a glutathione-sensitive (S-S) cleavable linker.  Intraperitoneally (abdominal cavity) injected CBX-12 localized to tumors selectively in a mouse xenograft model of Her2-overexpressing breast cancer.


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.!



Friberg S, Nyström A. Cancer Metastases: Early Dissemination and Late Recurrences.  Cancer Growth Metastasis. 8:43-9 (2015).  PMID: 26640389

Gayle S, Aiello R, et al. Tumor-selective, antigen-independent delivery of a pH sensitive peptide-topoisomerase inhibitor conjugate suppresses tumor growth without systemic toxicity.  NAR Cancer.  3:zcab021 (2021).  PMID: 34316708

Meng S, Tripathy D, et al. Circulating tumor cells in patients with breast cancer dormancy.  Clin Cancer Res. 10:8152-62 (2004).  PMID: 15623589

Pedersen RN, Esen BÖ, et al. The Incidence of Breast Cancer Recurrence 10-32 Years After Primary Diagnosis.  J Natl Cancer Inst. 114:391-399 (2022).  PMID: 34747484

Walter CW, Gillespie DR. Metastatic hypernephroma of fifty years' duration.  Minn Med.  43: 123-5 (1960).  PMID: 13782941

Wyatt LC, Moshnikova A, et al. Peptides of pHLIP family for targeted intracellular and extracellular delivery of cargo molecules to tumors.  Proc Natl Acad Sci U S A. 115:E2811-E2818 (2018).  PMID: 29507241