Micromet Leads In Bispecific Antibodies, Watch For DARTs

Bispecific antibodies are another front in the race to modify therapeutic antibodies for increased efficacy. Unlike normal antibodies, bispecifics are able to recognize and bind two or even three different antigens. The modified antibodies have new attributes allowing them to perform functions inconceivable for standard antibodies.

The pursuit of bispecific antibodies began at least two decades ago but was hampered by the difficulty in producing the novel agents, especially in high quantity and purity. Scientists attempted to create bispecifics using multiple strategies, from using different Fab arms on the same antibody, to chemical crosslinking of different antibodies or fragments, to minimally sized molecules.

Micromet was one of the first to solve the problems vexing developers of bispecific antibodies. It developed a platform technology termed BiTE (bispecific T-cell engagers), potent single-chain antibodies with bispecific capabilities.

The BiTE recruit T-cells through CD3 and are active at 10-100pg/ml concentrations. A single T-cell is capable of killing multiple cancer cells decorated with small number of BiTE. They are capable of directing T-cell killing without the need to pre- or co-stimulate the cells. It is thought this is because BiTE induce cytoytic immunological synapses between cytotoxic T-cells and target cells that are similar to normal T-cell synapses.

There are now several bispecific antibodies from Micromet in clinical trials, both wholly owned and in collaboration with pharma partners. Its most advanced candidate is blinatumomab, designed to redirect T-cells toward CD19 positive B-cells. Blinatumomab is in pivotal trials for minimal residual disease (MRD) positive lymphoblastic leukemia; MRD results when front-line chemotherapy fails to clear all the leukemia cells from a patients bone marrow. The drug is also being tested in non-Hodgkin’s lymphoma (NHL) patients.

Data for blinatumomab was most recently presented at ASH in December last year; it was quite impressive. Of 20 evaluable patients for MRD Acute Lymphoblstic Leukemia (ALL), 80% achieved MRD negativity, and 60% registered hematologic disease free at 27.5 months of follow-up.

The pivotal blinatumomab trial is a single armed, open label trial set to accrue 130 MRD positive patients with ALL. The primary endpoint is MRD response rate at 6 weeks. Secondary outcome measures include hematological relapse-free survival, overall survival, and overall adverse effects. It was initiated in Q3 2010.

Early NHL results were also quite good. At 60 microgram/square meter, 18 of 22 (82%) patients with relapsed non-Hodgkin’s lymphoma achieved an objective response. There was one concerning issue of CNS events, but they appear to be reversible; it appeared to be linked to B-cell to T-cell ratio, patients with a higher B:T ratio had a low incidence of discontinuation due to CNS events. The company believes the effect can be detected early and managed with steroids.

Micromet has turned its success into lucrative collaborations with Pharmas including MedImmune, Sanofi-Aventis, and Boehringer. Its alliances have netted the company $131 million between 2006 to 2010 alone.

There is a surge in interest in bispecific antibodies. Micromet is closest to market in the US, but there is one already approved in the EU. Trion, in collaboration with Fresenius had developed the bispecific antibody catumaxomab, which was approved in 2009. The drug consists of half a mouse anti-CD3 antibody together with half a rat anti-EpCAM antibody. It is considered a tri-functional antibody; Catumaxomab binds CD3 positive T-cells, EpCAM positive tumor cells, as well as other immune cells via its Fc chain.

Other contenders include Macrogenics and the start-up f-star. Both made splashy headlines in recent days with big technology licensing deals. Macrogenics has its Dual-Affinity Re-Targeting (DART) technology. Their molecules are still in pre-clinical development but have already generated significant interest. An independent paper comparing DART and BiTE antibodies showed DARTs may be more potent in vivo.

Products from f-star are at a very early stage; its key differentiator is a Modular Antibody Technology format from which it can engineer single chain antibodies, diabodies, as well as full antibodies. A major attraction of their technology is its ease of production.

Antibody technology is changing at a rapid clip due to advances in genetic engineering. It has taken the industry some 25 years, but the goal is near. Bispecific antibodies will soon take their place alongside “regular” therapeutic antibodies; BiTEs from Micromet will lead the charge.

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