Hemocyanine / KLH

biosyn is a world leader in the manufacture of high quality, clinical / GMP and research grade hemocyanin products (IMMUCOTHEL® and VACMUNE® liquid) derived from the hemolymph of the sea snail, Meghathura crenulata, also commonly known as the Giant Keyhole Limpet. The hemocyanin derived from this snail is widely known as Keyhole Limpet Hemocyanin, in short KLH.

IMMUCOTHEL® – for recurrence prevention of superficial urinary bladder carcinomas

Superficial bladder cancer: Instillation therapy with IMMUCOTHEL® for recurrence prevention

Bladder cancer is the second most common malignancy of the urogenital tract and the fourth most common type of cancer in men. The standard treatment for preventing post-TUR recurrences has been instillation therapy with cytostatics and/or the immunotherapeutic agent BCG. Both are associated with good efficacy, but also with certain side effects. The availability of BCG is currently limited.

IMMUCOTHEL® is a well-tolerated and efficacious immunotherapeutic agent for instillation therapy to prevent recurrences of superficial bladder cancer. Its benefits lie in the fact that its efficacy is equipotent to chemo- or immunotherapy with BCG but has markedly fewer side effects.

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Compared with BCG and Mitomycin, IMMUCOTHEL® shows the lowest therapy failure rate (1%), a 10 times lower side effect rate (5%), 0% allergic reactions and a 17% five-year disease-free survival rate. Details on recurrence prevention in superficial urinary bladder carcinomas below:

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IMMUCOTHEL®: Significant extension of the recurrence-free interval

The most frequent variant of KLH consists of 20 subunits that form two connected rings (didecamers) with a molecular weight of about 8 million Dalton. The dissociated subunits of KLH form the immunocyanin with a molecular weight of about 400 KiloDalton. 

If one administers immunocyanin to patients, this results in the body's confrontation with hundreds of xenogenic epitopes of this molecule and triggers the activation of the patient's immune system. The protein structures of the immunocyanins induce increased activation or synthetization of T-helper cells, cytotoxic T-suppressor cells, IFN-α, IFN-γ, IL-1a, and IL-2, macrophages and NK cells are stimulated. For patients with superficial urinary bladder carcinoma, the recurrence-free interval is significantly (≥ 100%) extended by KLH (IMMUCOTHEL®) (Fig. 1).

Recurrence prevention for superficial bladder carcinoma with KLH
Abbildung: Effektivität in Relation zur Nebenwirkungsrate von Arzneimittel zur Verhinderung von Rezidiven eines oberflächlichen Blasenkarzinoms

KLH: Mechanism of action

  • KLH stimulates the immune system
  • KLH has a direct cytotoxic effect
  • Strong KLH immunogenicity is based on the attached oligosaccharides

The exact mechanism of action of KLH is not yet known. KLH itself shows moderate anti-carcinogenic activity [1]. However, the effect of KLH on superficial bladder carcinomas is based on its capability of stimulating the immune system [2] (Fig. 1).

IMMUCOTHEL treatment of dendritic cells with KLH.png
IMMUCOTHEL® Treatment of dendritic cells with KLH.png

The strong immunogenicity of KLH is probably based on the numerous attached oligosaccharides that account for about 4% of the molecular mass of KLH [3] (Fig. 2).

IMMUCOTHEL KLH expresses different oligosaccharides
IMMUCOTHEL KLH expresses different oligosaccharides

Different mechanisms of action play a role here: on the one hand a non-specific stimulation of the immune system [4], and on the other hand the stimulation of cytotoxic T-cells. The third mechanism of action is the induction of antitumoral antibodies.

After an immunization with KLH, mice produced antibodies that bind tumor-associated oligosaccharide antigens [5]. In addition, studies with bladder carcinoma patients showed an increase of anti-KLH antibodies in patients who responded to KLH treatment [6].

An additional study showed that KLH expressed Gal(beta 1-3) GalNAc-bearing oligosaccharides. The immunization of rats with KLH induces the production of anti-Gal(beta 1-3)Gal-NAc antibodies. Since bladder carcinomas express cross-reactive Gal(beta 1-3)GalNAc epitopes (also called Thomsen-Friedenreich antigens), the effectiveness of immunotherapy with KLH for superficial bladder carcinoma is most likely based on this fact [7].

Sources:

  1. McFadden DW, Riggs DR, Jackson BJ, Vona-Davis L. Keyhole limpet hemocyanin, a novel immune stimulant with promising anticancer activity in Barrett’s esophageal adenocarcinoma. Am J Surg. 2003 Nov; 186(5): 552–555.
  2. Presicce P, Taddeo A, Conti A, Villa ML, Della Bella S. Keyhole limpet hemocyanin induces the activation and maturation of human dendritic cells through the involvement of mannose receptor. Mol Immunol. 2008 Feb; 45(4): 1136–1145.
  3. Kurokawa T, Wuhrer M, Lochnit G, Geyer H, Markl J, Geyer R. Hemocyanin from the key- hole limpet Megathura crenulata (KLH) carries a novel type of N-glycans with Gal(beta1-6) Man-motifs. Eur J Biochem. 2002 Nov; 269(22): 5459–5473.
  4. Tzianabos AO. Polysaccharide immunomodulators as therapeutic agents: structural aspects and biologic function. Clin Microbiol Rev. 2000 Oct; 13(4): 523–533.
  5. May RJ, Beenhouwer DO, Scharff MD. Antibodies to keyhole limpet hemocyanin cross-react with an epitope on the polysaccharide capsule of Cryptococcus neoformans and other carbo- hydrates: implications for vaccine development. J Immunol. 2003 Nov 1; 171(9): 4905–4912.
  6. Jurincic-Winkler CD, von der Kammer H, Beuth J, Scheit KH, Klippel KF. Antibody response to keyhole limpet hemocyanin (KLH) treatment in patients with super cial bladder carcinoma. Anticancer Res. 1996 Jul-Aug; 16(4A): 2105–2110.
  7. Wirguin I, Suturkova-Milosević L, Briani C, Latov N. Keyhole limpet hemocyanin contains Gal(beta 1-3)-GalNAc determinants that are cross-reactive with the T antigen. Cancer Immunol Immunother. 1995 May; 40(5): 307–310.
  8. Gatsogiannis C, Markl J. Keyhole limpet hemocyanin: 9-A CryoEM structure and molecular model of the KLH1 didecamer reveal the interfaces and intricate topology of the 160 functional units. J Mol Biol. 2009 Jan 23; 385(3): 963–983.