Targeted Chemotherapy
Platform

Targeted Chemotherapy Platform

Therapy Indication Partners Discovery Pre-Clinical Phase I Phase II
ACT-901
(AFP + paclitaxel)
Targeted Oncology
Solid and liquid tumors
Collaboration University Health Network
 
ACT-902
(AFP + thapsigargin)
Targeted Oncology
Solid and liquid tumors
Collaboration University Health Network
 
ACT-903
(AFP + linker + maytansine)
Targeted Oncology
Solid and liquid tumors
Collaboration Polytherics (Abzena) U.K.
 

Lead Assets

ACT-901 (AFP + paclitaxel)

  • Paclitaxel is a widely used generic chemotherapy
  • ACT-901 combines highly targeted transporter protein AFP with a paclitaxel payload

ACT-902 (AFP + thapsigargin)

  • Thapsigargin is a potent generic cytotoxic drug equally effective against aggressive and indolent tumors
  • ACT-902 combines highly targeted transporter protein AFP with a thapsigargin payload

ACT-903 (AFP + linker + maytansine)

  • Maytansine is a potent microtubule-targeted cytotoxic drug that induces mitotic arrest and kills tumor cells
  • ACT-903 combines highly targeted transporter protein AFP with a maytansine payload using cleavable linker

Targeted Chemotherapy

Alpha Fetoprotein (AFP)

  • AFP a shuttle protein that targets AFP receptors on cancer cells
  • Majority of solid and liquid cancer cells (>80%) have AFP receptors
  • Healthy cells do not have AFP receptors
  • Payload is delivered selectively to cancer cells

Benefits

  • Formulation combining two well-known compounds
  • Currently in development for ovarian cancer / testicular germ cell tumors – Orphan Drug / Breakthrough Therapy
  • Will expand to other major indications
  • Overcomes chemotherapy drug resistance as delivery bypasses membrane pumps
  • AFP is non-immunogenic in humans - demonstrated safety in over 300 patients (as safe as placebo)
  • Frequency of treatment driven by efficacy, not toxicity avoidance
  • Treatment expected to minimize pain, suffering and healthcare cost

Target Product Profile

  • Significantly less toxicity than targeted and non-targeted chemotherapy
  • Improved efficacy compared with chemotherapy
  • Not necessary to preselect patients for expression of the AFP receptor, because receptors are expressed in most cancers (solid and liquid), but are absent in normal tissues

Evidence of Efficacy

In Vitro Study

Overcoming Multidrug Resistance In Human Ovarian Cell Line

A study on chemo-resistant ovarian carcinoma cell line SKVLB demonstrated that is takes 10 times more dox to kill 50% of the cells in the resistant cell line than with AFP-Dox which seems to be able to overcome the resistance by binding to receptors found on the resistant cells and transporting dox directly into the cell bypassing the cell membrance pumps.

Moskaleva et al. (1997), Cell Biol. Internat., 21, 793-799

In Vivo Tumor Volume

In this study 3 groups of mice were treated with either saline or with equal doses of paclitaxel (Taxol®) delivered either as a conventional paclitaxel formulation (red line) or carried by AFP (ACT-901) (blue line). The graph illustrates that tumor growth is significantly reduced when paclitaxel is delivered by AFP (ACT-901) compared to the same dose of free paclitaxel.

UHN, Princess Margaret Cancer Centre

In Vivo Survival Study

In this study several groups of mice were treated with various doses of paclitaxel (Taxol®) or ACT-901 (AFP + paclitaxel). The black line shows the control group that was given only saline. All mice were dead by day 24.

The 2 red lines show survival of mice given low (dotted red line) or high (solid red line) of paclitaxel. Low dose paclitaxel had no effect and did not improve survival rates.

The same low paclitaxel dose (blue line) delivered as ACT-901 (AFP + paclitaxel) significantly improved survival and was even better than a high dose paclitaxel.

There were 7 mice per group in this study. Low dose paclitaxel and ACT-901 (AFP + paclitaxel) were given every other day for 3 weeks at the same dose of paclitaxel, while in high dose paclitaxel group treatment was daily for 3 weeks.

Mice in the high paclitaxel group (solid red line) showed signs of severe toxicity, with weight loss and lack of normal grooming behaviour and excessive irritability. The ACT-901 (AFP + paclitaxel) group exhibited no signs of toxicity. There was also significant vein sclerorsing in the high paclitaxel group but not in the ACT-901 (AFP + paclitaxel) group.

UHN, Princess Margaret Cancer Centre

In Vivo Xenograft Study

In this study 2 groups of mice were treated with saline (control group) or ACT-902. Dotted lines show individual tumor volumes in control mice. All mice were dead by day 24. Solid lines show changes in tumor volumes of mice treated with ACT-902.

5 out of 6 ACT-902 treated tumors show complete regression of tumors by day 7 of treatment with no further growth thereafter. One tumor was unresponsive and continued to grow.

It should be noted that POP-92 cancer cells are from patient with BRAF mutated colorectal cancer. This type of cancer is highly resistant to chemotherapy resulting in poor prognosis for patients with this cancer type.

UHN, Princess Margaret Cancer Centre