Overview
Perseis Therapeutics Ltd is currently progressing three associated research programs aimed at targeting cancers (breast, prostate, colorectal and gastric cancer) with monoclonal antibodies. The three targets are the Trefoil Factor family 1 and 3 proteins (TFF-1 and TFF-3) and Growth Hormone (GH). At the end of the first development milestone, we will have proven in vivo efficacy of antibodies against these targets and will be able to select the potential therapeutic candidates to take forward into further development or partnering discussions.
Trefoil Factors
Trefoil factors are classical estrogen-regulated proteins and have been used as markers of estrogen gene regulation. TFFs are also regulated by a number of other factors, including GH, IGF-1, TGF-β, EGF, FGF and other oncogenic stimuli. TFFs act as growth factors, and promote cell survival and motility. Recently, TFFs have been linked to cancers, as they play a role in oncogenic growth, cancer cell survival, and metastatic extension of solid tumours. Importantly, high serum TFF levels have been shown to correlate with both cancer occurrence and poor prognosis. Conversely, the neutralisation of TFFs (using antibodies) produces a loss of cancer cell viability for a number of solid cancer types. A review of the use of TFF inhibition to treat cancer was recently published by Professor Peter Lobie and colleagues. Perseis is developing monoclonal antibodies against two members of the TFF family: TFF-1 and TFF-3. There is considerable evidence that the neutralisation of either TFF would provide therapeutic benefit in a variety of cancers.
TFF-1
In vitro studies with polyclonal antibodies raised against TFF-1 in mice have confirmed that neutralisation of TFF-1 protein reduces the viability of both MCF7 and T47D mammary carcinoma cells, relative to cells grown in the presence of an IgG (non-specific) control antibody. Data from polyclonal antibodies and monoclonal antibodies to TFF-1 increase apoptosis of MCF7 cells, implicating apoptosis as one mechanism of action for the reduced cellular viability observed in vitro in these cells.
TFF-3
In vitro cell viability studies with monoclonal antibody (mAb) against TFF-3 have shown a mouse mAb was capable of reducing viability of mammary and colorectal cancer cell lines. In vivo, the same antibody was used in a xenograft tumour growth model in immunocompromised mice and shown to reduce tumour volume over a two week treatment period. In addition, in vivo studies with anti-TFF-3 antibodies administered in tamoxifen resistant cancers have demonstrated a significant reduction in tumour mass.
Growth Hormone
The oncogenic potential of human growth hormone (hGH) has been known for some time, and recently reviewed by Lobie and colleagues. Endocrine hGH released from the anterior pituitary has a number of functions, not least of which is the regulation of somatic growth mediated by the GH receptor and stimulation of hepatic IGF-1 secretion.
However, within the last two decades it has become better understood that in addition to the classical pituitary actions of hGH, the hormone has important paracrine and autocrine actions. One important action is oncogenesis: acromegaly patients as well as those who are taller show increased incidence of numerous cancers, providing a clear correlation between circulating hGH and cancer. Upregulated hGH has been observed in endometrial adenocarcinoma and colonic cancers. In in vitro studies forced expression of hGH leads to carcinoma cell proliferation, anchorage-independent growth. In vivo forced expression of HgH leads to tumour formation in immune-compromised mice. When hGH is applied exogenously , in a way that mimicks the actions of classical endocrine hGH release, it does not appear to be oncogenic in the same manner. This suggests the oncogenicity of hGH is limited to an autocrine action.
Perseis has demonstrated that targeting hGH with neutralising antibodies has a strong potential therapeutic advantage. Patents covering these findings are pending.
Milestones
Over the next year, the Perseis team will select 2-3 antibodies that have shown the most promise in preclinical trials to take forward into further development or partnership. The first stage of development for these compounds is the creation of a large batch of monoclonal antibodies to TFF-1, TFF-3 and hGH. Once these antibodies are generated, they will be screened initially against various in vitro cancer models in the lab to select the most potent antibodies to be tested in animal models of human cancer. The selected antibodies will be then scaled up to produce a sufficient volume of antibodies to be tested in an in vivo model. Cross-reactivity and mechanism of action studies will also be conducted in parallel.