A handful of antibody-drug conjugates have now reached the market and plenty more are under development
There has been a lot of interest in recent years in antibody–drug conjugates, particularly as potential cancer therapies. A handful have reached the market for various different malignancies, and many others are under development, including Pfizer’s inotuzumab ozogamicin, originally developed in collaboration with Celltech (now UCB).1 It is being investigated as a potential treatment for haematological malignancies. The ADC comprises the humanised monoclonal antibody inotuzumab, which is directed against the cell surface antigen CD22, which is joined to the calicheamycin-derived cytotoxic drug ozogamicin via a linker. CD22 is expressed in about 90% of all B-cell malignancies./p>
In a Phase II trial, a total of 90 patients with refractory and relapsed acute lymphocytic leukaemia were treated.2 The first 49 of these were given single intravenous doses of 1.3 to 1.8mg/m2 of the ADC every three to four weeks. The subsequent 41 patients were given weekly doses, starting with 0.8mg/m2 on the first day, then further doses of 0.5mg/m2 on days 8 and 15, every three to four weeks. The schedule was altered because of higher in vitro activity with more frequent exposure.
Two-thirds of the patients were in salvage 2 or beyond, and 17 achieved a complete response, 27 had a complete response with no platelet recovery, and a further eight had a bone marrow complete response with no recovery of counts. This gave an overall response rate of 58%. Median survival was just over 6 months overall, with 5 months for the single-dose schedule, and 7.3 months for the weekly schedule. The weekly dose schedule appeared to be less toxic, with reversible bilirubin elevation, hypotension and fever observed less frequently. Response rates were similar across both dosing regimens. Allogenic stem cell transplantation was undergone by 36 of the patients, and veno-occlusive disease less frequent after the weekly schedule.
Pfizer subsequently announced via press release that the first primary endpoint of a Phase III trial has been met. This was a higher complete haematological remission patients with relapsed or refractory CD22-positive acute lymphoblastic leukaemia, compared with standard of care chemotherapy. In the open label, randomised study, treatment with the ADC was compared with a defined set of chemotherapy choices. A total of 326 subjects were given weekly intravenous doses of the ADC for three weeks for a 3–4 week cycle, for up to six cycles. The options included fludarabine, cytarabine and G-CSF; high dose cytarabine; or cytarabine in combination with mitoxantrone. The study is still underway to collect information about overall survival rates. It is being investigated in other haematological malignancies, including B-cell non Hodgkin lymphoma and diffuse large B cell lymphoma. Trials continue.
1. J.F. DiJoseph et al. Cancer Chemother. Pharmacol. 2011, 67, 741
2. H. Kantarjian et al. Cancer 2013, 119, 2728