Wednesday, November 25, 2009


TRU-016 is described as “a single chain anti-CD37 Fc fusion molecule that displays pro-apoptotic and Fc-dependent cellular cytotoxicity activities against CLL cells and NHL lines.” CD37 is a tetraspanin transmembrane family protein that is strongly expressed on the surface of mature human B-cells and transformed mature B-cell lymphoma and leukemia cells, including CLL cells. It is expressed minimally or is absent on normal T-cells, natural killer cells, monocytes, and granulocytes.

It must be twenty years since George Stevenson and I first attempted to treat CLL with anti-CD37 monoclonal antibodies. One of the things that we found was that when we produced a univalent chimeric Fab molecule with an Fc attached we enhanced the killing of CLL cells (Mechanisms in removal of tumor by antibody. Stevenson GT et al Cell Biophys. 1994; 24-25:45-50).

There are two papers at ASH on TRU016 and CLL.

It has been previously reported that the chimeric precursor of the fully humanized TRU-016, induced apoptosis in CLL B cells through a novel, caspase-independent pathway. It also showed potent in-vivo activity in a SCID xenograft mouse model. Apart from its direct cytotoxicity, it mediated antibody-dependent cellular cytotoxicity (ADCC) by NK cells both in vitro and in vivo. Recently, in an attempt to enhance the ADCC function, a new variant has been created with a modification of the glycosylation of the Fc portion of the molecule. This has been shown to exhibit enhanced binding to both low- and high-affinity molecular variants of human CD16 (FcRIII) and augmented ADCC potency when compared to its previous formulation. In the study reported at ASH the molecule with the modified glycosolation resulted in 2 to 4 fold increased NK cell mediated ADCC function. This suggests that improved glycosolation will enhance the effect of TRU016

A phase I study with TRU-016 in patients with relapsed and refractory CLL or SLL who had adequate organ function and platelets > 30,000/mm3. Seven doses and two different schedules have been studied. The planned doses range from 0.03 mg/kg to 10 mg/kg IV once a week for 4 doses. The second schedule tests 3, 6 or 10 mg/kg on days 1, 3 and 5 the first week followed by 3 weekly doses.

To date, 32 patients have been treated. In the weekly treatment schedule: 1 patient in each of the first 3 cohorts (0.03, 0.1, and 0.3 mg/kg); 3 patients at 1 mg/kg, 4 patients at 3 mg/kg, 7 patients at 6 mg/kg, and 5 patients at 10 mg/kg. In the TIW loading dose schedule: 8 patients at 3 mg/kg and 2 patients at 6 mg/kg. Genomic data is available for 27 patients and 19 have high risk genomic features [del(17p13.1), n=10, del(11q22.3), n=7, both=2]. The maximum tolerated dose (MTD) has not been reached. 12 serious adverse events have been reported and three may have been related to study drug, including grade 4 neutropenia, Herpes Zoster and ITP. Mild (grade 1-2) infusion toxicity has been observed.

Beginning with the 0.3 mg/kg dose, evidence of biological activity has been observed: one partial response (PR) in a patient with 17p del, two patients with leukemia cutis had partial or complete clearing, and in patients with peripheral lymphocytosis the median reduction was 83% (range 13% to 98%). Improvement in cytopenias has also been observed. Enrollment to cohort 8 and 11 is complete and further up-to-date data will be presented.

Our experiments with anti-CD37, which were hampered by our inability to produce enough of it in the University laboratory, concluded that it was possible to clear cells from the peripheral blood, but we only obtained one PR in the patients that we treated. I remain to be convinced that TRU016 performs better in patients than the native antibody.

1 comment:

Anonymous said...

The proof will be in the pudding. It is not knocking anyone's socks off as yet.