Research Publications

GBR 830: An antagonistic anti-human OX40 mAb with potent suppressive effect on pathological immune responses

OX40 is a costimulatory TNFR-superfamily receptor expressed almost exclusively on activated T lymphocytes and not on naïve or resting memory cells. OX40 signaling can enhance proliferation, survival and effector functions of T cells with a more pronounced effect on late, chronic and memory responses. Many studies have indicated that OX40 may play a central role in various T-cell mediated pathological immune responses, thus implying a therapeutic potential for antagonistic antibodies targeting OX40. However to date no antagonistic antibodies targeting OX40 have been published.

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Upstream process development for GBR 1302, a bispecific antibody based on Glenmark's Proprietary BEAT®(Bispecific engagement by Antibodies based on T Cell Receptor) format

Glenmark Pharmaceutical’s BEAT® platform is a novel bispecific heavy chain heterodimerization platform based on a unique concept of bio-mimicry. Using our BEAT® platform, we have developed a BEAT antibody – GBR1302 –designed to effectively recruit cytotoxic T cells against HER2 positive breast cancer cells including the trastuzumab-resistant breast cancer cell lines. GBR 1302 is composed of three different subunits (HC, scFV-FC and LC) that are expressed in recombinant CHO-S cells. Herein, we describe the upstream process development which lead to an industrial scalable process.

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GBR1302 - BEAT® bispecific antibody for the treatment of HER2 positive cancers

We have generated a novel bispecific BEAT® antibody (GBR1302) which can simultaneously bind HER2 (+) tumor cells and CD3ε on cytotoxic T cells. GBR 1302 potently re-direct T cells to HER2 positive cancer cells showing strong tumor cell lysis activity. The differential killing efficacy of HER2 (3+) and HER2 (0+) cells reveals an excellent safety-efficacy margin. This essential feature supports the assumption that in patients with HER2 (3+) cancers, a dose of GBR 1302 that will kill tumor cells but not normal cells can likely be achieved. Furthermore, GBR 1302 shows the following attributes that warrant their clinical investigation; BEAT® GBR 1302 bispecific antibody can be produced using standard antibody technology with industrial relevant expression yield. GBR1302 bispecific antibodies have unique advantages which also include a built-in purification system for manufacturing.

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Upstream process development for GBR 1302, a bispecific antibody based on Glenmark's Proprietary Beat® format

The BEAT platform was designed for the robust, rapid and cost-effective development of bispecific antibodies. The format maintains all the benefits brought by an antibody scaffold whilst bringing a “plug and play” approach to the generation of therapeutic products.

GBR 1302 is the first BEAT developed by Glenmark for the treatment of HER2+ cancers

Following a fast-track upstream process development a 5L stirred-tank bioreactor process could be established for GBR 1302 stable cell lines. This process was successfully scaled up to 50L and 250L scale without loss of performance. The level of bispecific product formation was not affected by the scale of production. The quality attributes of GBR 1302 were found very similar compared to a standard IgG produced using the same host cell (typical CHO glycosylation pattern, pI, level of aggregation < 2%)

The excellent manufacturing attributes of GBR1302 allows further clinical development as a treatment for HER2 positive cancers. Entry in phase I is expected in 2015.

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