Monoclonal Antibody Therapy (2012)

Also see: Targeted treatments

Also see: Recently identified genetic alterations and the TARGET initiative (2011)

Also see: New Treatments for ALL

2012: The future role of monoclonal antibody therapy in childhood acute leukaemias. Barth M, Raetz E, Cairo MS. Br J Haematol, epub 2012 Aug 13. Abstract.

The following information is from the Barth et al paper (above). It's my "lay summary" of the parts of this paper that are of interest to parents of children with ALL.

A monoclonal antibody (mAb) is a type of protein made in a laboratory that can bind to various substances in the body, including tumor cells. The first major advance in the use of mAb therapy was the US FDA approval of the use of rituximab for the treatment of relapsed and refractory lymphoma in 1997. In our context of ALL, the mAbs (abbreviation for monoclonal antibodies) of interest bind to specific cell surface antigens of leukemia cells, e.g., CD 19, CD20, CD33, CD40, HLA-DR, and CD52. Some mAbs will cause cell death if they simply bind to a leukemia cell. These are called "unconjugated" antibodies.

But monoclonal antibodies alone do not always cause cell death. A tactic of the researchers is to connect a mAb to a cell-killing (cytotoxic) agent, such as an immunotoxin, chemotherapeutic agent, or a radioactive molecule. The conjugated mAbs will then bind to specific cell surface antigens of leukemia cells and deliver the cytotoxic agent. Another class of mAbs employ bispecific antibodies that are directed to two antigens and recruit immunologically active cells to the leukemia cells.

mAbs have advantages over chemotherapy because they specifically target tumor cells, employ mechanisms of action that are different from chemotherapy, and they have a generally favorable safety profile. This is important, because current intense ALL chemotherapy regimens have often reached their limit of tolerability.

That's the hopes in developing mAbs. In practice, a few of these are indeed in the pipeline for treatment of childhood ALL (see the next paragraphs). If you are interested, I suggest you get the full text version of this paper. It includes good illustrations of how mAbs work, a table that explains their nomenclature, and a table of the various cell surface antigen targets in pediatric leukemias along with the mAbs in development.

Epratuzumab (CD22, unconjugated)

Epratuzumab targets a domain of CD22, an antigen expressed in over 95% of pediatric ALL cases. In a phase I trial, epratuzumab was used in combination with chemotherapy for children and young adults on the COG trial ADVL04P2 (NCT00098839). The results showed complete remissions in 9 of 15 patients. A phase II trial did not show a dramatic advantage over standard chemotherapy treatments, however, epratuzumab treatment resulted in significantly lower MRD values. Quote from this Barth article: "Epratuzumab was tolerated well with no increase in baseline toxicity over what was historically observed with chemotherapy alone. Epratuzumab is currently being tested in combination with cytarabine and clofarabine in adult patients with relapsed or refractory ALL."

Inotuzumab ozogamicin (CD22, conjugated)

Inotuzumab ozogamicin (CMC-544) is a mAb directed to CD22 that is linked to calicheamicin, an anti-tumor antibiotic. Quote from Barth article: "The clinical activity of this agent has recently been demonstrated in adults and a small number of children 16 years of age or younger with relapsed and refractory CD22-positive ALL." Responses to this agent alone (no other chemotherapy agents used) showed a response rate of 57%. This result suggests that inotuzumab ozogamicin might be promising for further study in children with ALL.

HA22 (CD22, conjugated)

HA22 is a "second-generation anti-CD22 immunotoxin" that is in phase I trials in children and young adults with relapsed/refractory CD22+ lymphoblastic leukemia.

Blinatumomab (CD19, bispecific)

Blinatumomab is a "new bi-specific single-chain antibody construct that binds CD19 and CD3. It was designed to direct CD3+ cytotoxic T-cells to CD19-expressing leukemic blasts." Blinatumomab has been used in a small number of children with relapsed/refractory ALL. In a report of the treatment of three children, all three achieved molecular remission. A trial is open within the COG (NCT01471782).