CM101: Tumor Capillary Disruption Mechanism of Action:
Mechanism of action for CM101, a 270,000da molecular weight polysaccharide, the Group B Streptococcal Toxin (GBS Toxin) as an immune activator targeting tumor neovasculature for disruption: The following description for the molecular target HP59 has been uploaded into a Wikipedia page under “HP59” (see Links Page) which describes the endothelial luminal lectin receptor for CM101.
Essentially, all tumor vasculature examined by the Hellerqvist group, cited below, expressed a lectin protein marker HP59, discovered, isolated, cloned and expressed, and described in detail below (see Fu, et al. Links Page). CM101, the biological therapeutic GBS Toxin polysaccharide binds to the HP59 lectin and activates complement. An inflammatory cytokine cascade then recruits CD69+ activated granulocytes which disrupt the tumor neovasculature and surrounding tumor.
This is a different paradigm than simply attempting to inhibit vascular growth with VEGF or tyrosine kinase interventions. CM101 targets the tumor neovasculature for immune disruption. The capillary endothelial cells that express HP59 are believed to be entirely host-derived, therefore the tumor may not be able to mutate an escape mechanism.
An IND-based FDA approved Phase I clinical trial has been performed and published in 1997 (6) which showed about 33% effectivity in stage 4, refractive cancer patients with 4-5 month expected lifespans. Of the Phase I patients, one was completely cured of Classic Kaposi’s Sarcoma, and followed for 10 years. One 43 year old female with metastases from duodenal cancer saw all tumors disappear except a large one that shrunk 90% and was excised for examination. She was treated 7 months later successfully for a new metastasis and again 18 months later for a new metastasis, and survived 4 years. A third patient with 6,9, 12 cm tumors in the liver saw tumor shrinkage and halted progression and survived another 18 months. Other patient improvements were seen, extremely unusual in a phase I trial.
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Details of the Tumor Capillary Disruption mechanism of action of CM101, its receptor HP59 and relevant publications:
HP59is a tumor capillary endothelial marker protein(7 or 12 transmembrane domains)which has been identified as the lectin receptor for the 270,000da complex polysaccharide Group B Streptococcal Toxin (GBS Toxin) molecule known as CM101 CM101 is the etiologic agent for "Early Onset Disease", which disrupts capillaries in the lungs of newborns if sepsis is acquired only in the first 5 days postnatal. Hellerqvist, et al. coined the term "pathological angiogenesis" to distinguish between HP59-expressing, and non-HP59-expressing capillaries in the citations below, and several other researchers have also used this terminology. HP59 appears to be expressed in all solid tumor vasculogenesis, since capillaries in all tumor tissues examined were positive for anti-HP59 antibodies and Von Willebrand factor (vWF) antibodies, while in normal tissues only vWF staining was observed
Within 5 days after birth, HP59 lectin is expressed on neonate lung capillary endothelium, providing a receptor for CM101, the CM101-HP59 complex then activates complement to initiate an inflammatory cytokine cascade which recruits CD69-positive activated granulocytes to destroy the capillaries and surrounding tissue. HP59 is expressed in the adult in wound healing, and in tumor angiogenesis, as shown in miceand humans. CM101 has been shown in a published Phase I, FDA-approved clinical trial under IND to have clinical safety and effectivity on select stage IV cancer patients, specifically disrupting tumor vasculature.
The gene for HP59 contains, entirely within its coding region, the Sialin Gene SLC17A5(Solute carrier family 17 (anion/sugar transporter). Member 5, also known as SLC17A5or sialin is a lysosomal membrane sialic acid transport protein which in humans is encoded by the SLC17A5 gene on Chromosome 6, and appears to be important in CNS myelination. HP59 has a transcription initiation site 300bp upstream of the initiation site for the Sialin Gene SLC17A5, and encodes 41 additional aminoacids at the Amino-terminal. Thus, using an upstream transcription initiation site, and thus a different start codon, HP59, incorporating the Sialin gene product, becomes a pathologic capillary endothelial cell luminal membrane protein with unknown function, which the GBS Toxin CM101 specifically targets for disruption. Endothelial involvement is indicated by levels of Soluble E-Selectin.
1) Fu, C.; Bardhan, S; Cetateanu, N.D.; Wamil, B.D.; Wang, Y.; Yan, H-P.; Carter, C.E.; Shi, E. et al. (2001). "Identification of a Novel Membrane Protein HP59 with Therapeutic Potential as a Target of Tumor Angiogenesis". Clinical Cancer Research 7 (12): 4182–4194.
2) Sundell, H.W.; Yan, H.-P.; Wu, K.; Wamil, B.D.; Gaddipati, R.; Carter, C.E.; Stahlman, M.T.; Hellerqvist, C.G. (2000). "Isolation and identification of group B ß-hemolytic streptococcal (GBS) toxin from septic newborn infants". J. Pediat 137 (3): 338–344.
3) Yan, H.-P.; Carter, C.E.; Wang, E.; Page, D.L.; Washington, K.; Wamil, B.D.; Yakes, F.M.; Thurman, G.B. et al. (1998). "Functional studies on the anti-pathoangiogenic properties of CM101". Angiogenesis 2 (3): 219–233.
4) Nanney, L.B.; Wamil, B.D.; Whitsitt, J.; Cardwell, N.L.; Davidson, J.M.; Yan, H.-P.; Hellerqvist, C.G. (2001). "CM101 Stimulates Cutaneous Wound Healing Through an Anti-Angiogenic Mechanism". Angiogenesis 4 (1): 61–70.
5) Thurman, G.B.; Russell, B.A.; York, G.E.; Wang, Y.-F.; Page, D.L.; Sundell, H.W.; Hellerqvist, C.G. (1994). "Effects of GBS toxin on long-term survival of mice bearing transplanted Madison lung tumors". J. Can. Res. Clin. Oncol 120: 479–484.
6) DeVore, R.F.; Hellerqvist, C.G.; Wakefield, G.B.; Wamil, B.D.; Thurman, G.B.; Minton, P.A.; Sundell, H.W.; Yan, H.-P. et al. (1997). "A phase I study of the antineovascularization drug CM101". J. Clin. Can. Res. 3: 365–372.
Entrez Gene: SLC17A5solute carrier family 17 (anion/sugar transporter), member 5"
7) Haataja, L; Schleutker, J; Laine, AP; Renlund, M; Savontaus, ML; Dib, C; Weissenbach, J; Peltonen, L et al. (1994). "The genetic locus for free sialic acid storage disease maps to the long arm of chromosome 6". American journal of human genetics 54 (6): 1042–9.
8) Verheijen, FW; Verbeek, E; Aula, N; Beerens, CE; Havelaar, AC; Joosse, M; Peltonen, L; Aula, P et al. (1999). "A new gene, encoding an anion transporter, is mutated in sialic acidstorage diseases". Nature genetics 23 (4): 462–5.
9) Prolo, LM; Vogel, H; Reimer, RJ (2009). "The lysosomal sialic acid transporter sialin is required for normal cns myelination". J. Neurosci 29 (49): 15355–15365.
10) Wamil, Barbara D.; Thurman, Gary B.; Sundell, Hakan W.; Devore, Russell F.; Wakefield, Gail; Johnson, David H.; Wang, Yue-Fen; Hellerqvist, C. G. (1997). "Soluble E-selectin in cancer patients as a marker of the therapeutic efficacy of CM101, a tumor inhibiting agent, evaluated in phase I clinical trial". J. Can. Res. Clin. Oncol 123 (3): 173–179.