Arginine Deprivation Therapy Via Arginine Deiminase

1
Arginine Deprivation Therapy Via Arginine
Deiminase

• Mary Rose Stevens
• CHM 357, Smith College
• October 31, 2007

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Outline

• General topic cancer treatment
• Malignant melanoma, hepatocellular carcinoma
• Cell biology review
• urea cycle
• argininosuccinate synthetase (ASS)
• Arginine deiminase (ADI)
• discovery of anticancer effects
• arginine auxotrophy
• ADI structure and mechanism

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Outline

• Eligibility for ADI treatment
• ASS expression in cancer cell lines
• Resistance to arginine deprivation
• Drug design
• ADI-PEG 20
• Phase I/II trials
• Current status of ADI-PEG 20
• Companies, clinical trials
• Conclusion

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Malignant melanoma and HCC

• Kill most within 1 year of diagnosis
• 16,000 deaths/yr in the U.S.
• Melanoma is rapidly increasing
• Australia
• Urgent need for effective treatments
• Amino acid deprivation

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The Urea Cycle
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Argininosuccinate Synthetase

• Assumed biological molecule (left) and assymetric
  molecule (right) from source, E. coli

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Mycoplasma

• 2004 Ensor et al found that Mycoplasma kills
  cervical carcinoma and leukemia cell lines
• Mycoplasma contains the arginine-degrading
  enzyme, arginine deiminase (ADI)

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Arginine Deiminase (ADI)

• ADI (Psuedomonas aeruginosa) in complex with a
  reaction intermediate (left)
• ADI (Mycoplasma arginini) in complex with
  arginine (right)

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ADI Enzymatic Action
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Arginine to Citrulline and Ammonia via ADI
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ASS Expression in Cancer Cell Lines

• In 2007, Savaraj et al examined ASS expression
  levels in melanoma cell lines (A375, Sk-Mel-2,
  A2058, MEL-1220)
• Also examined ASS DNA levels lack of ASS
  expression is not from gene deletion

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Pegylated Arginine Deiminase (ADI-PEG20)

• Problem ADI has a short circulating half-life
  and high antigenicity
• Solution Polaris, Inc. developed a pegylated ADI
  (ADI-PEG 20), which has shown promise in clinical
  trials with melanoma patients

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Resistance to Treatment

• ASS expression in 4 melanoma cell lines before
  and after ADI-PEG20 treatment

In current
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Phase I/II HCC

• Auxotrophic for arginine
• ADI-PEG 20 is well-tolerated
• OBD 160 U/m2
• IM injection, once weekly
• Reasonable anti-tumor response rate
• Prolonged survival

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Phase I/II Stage IV Melanoma

• Auxotrophic for arginine
• ADI-PEG 20 is well-tolerated
• OBD 160 U/m2
• IM injection, once weekly
• Reasonable anti-tumor response rate (25)
• Prolonged survival (mean and median)

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Inhibition of NO Production

• Nitric oxide synthase (NOS) catalyzes nitric
  oxide (NO) production from extracellular arginine
• ADI-PEG 20 inhibited NO production
• No increased b.p. or h.r.
• Additional mechanisms of action

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Current Status of ADI-PEG 20

• Phoenix Pharmacologics, Inc.
• Polaris Pharmaceuticals, Inc.
• Complete
• Phase I, malignant melanoma (U.S.)
• Phase I and II, malignant melanoma (Italy)
• Phase I and II, HCC (U.S.)
• Phase I and II, HCC (Italy)
• In Progress
• Phase II, malignant melanoma (U.S.)
• Phase IIB / III, HCC (Italy)

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Current Status of ADI-PEG 20

• No human toxicities observed to date
• Medical benefit observed in HCC
• Primary market
• Metastatic melanoma - US (14000), EU (15000), AUS
  (15000)
• HCC - US (14000), EU (16000), Japan (125000)

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Conclusion

• ADI-PEG 20
• For cancer cell lines auxotrophic for arginine
• Effective in lowering plasma arginine
• Well tolerated
• Appears to have anti-tumor activity and prolong
  survival of patients with melanoma and HCC
• Multiple mechanisms

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References

• ADI-PEG 20. Polaris. Online http//www.polarispha
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  2007.
• ADI-PEG 20- Arginine deiminase conjugated with
  poly(ethylene) glycol. Phoenix Pharmacologics,
  Inc. Online http//www.phoenixpharmaco.com/ADIPEG
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