Misassigned (top) and corrected (bottom) structures of bioactive TIC10.

PIC FROM

http://pipeline.corante.com/archives/2014/05/22/a_horrible_expensive_and_completely_avoidable_drug_development_mixup.php

Don’t forget the chemistry
In a bit of a whoopsie it has come to light 1 that a compound TIC10, a stimulator of gene expression for TRAIL and in PhI/II clinical trials has in fact got an incorrect structure or rather the compound that was protected in the patent was assigned the incorrect structure. It was patented in a single compound patent 2 – which might ring alarm bells for some – were they really that confident they had the best compound. A quick look at the patent revealed large amounts of in vitro work but none in vivo again begging the question how good is this single compound. The compound had been identified by a group at Pennsylvania State University and licensed to Oncoceutics from screening of the NCI compound collection but the team, as reported, only attempted structural characterisation by MS. This would be unlikely to differentiate regioisomers which is what the problem turns out to be. It does however seem strange that the patenting error was not detected during resynthesis and scale-up for progression to the clinic. The error was picked up when a group from the Scripp’s 3 who synthesised the patented compound but found it inactive while they found the NCI batch to be active. They characterised the patented (inactive) and non-patented (active ex NCI) structures by crystallography and total synthesis. The corrected structure has now been patented by the Scripps group and licensed to Sorrento.
Of course this is all a bit embarrassing for those concerned but also more seriously could end up with extensive patent litigation, wasting money and discouraging investors from supporting the work until the patent situation is clarified causing delay in progressing the asset. Please please talk to medicinal chemsist early in a project this one looks like no one did which has led to an expensive mistake.

1. S. Borman Chem Eng News 2014, May 26 page 7
2. US Patent US8673923
3. N. T. Jacob et al Angew. Chemie. Int. Ed., Article first published online: 18 May 2014 DOI: 10.1002/anie.201402133

BOEHRINGER RECIPE

This synthesis from simpler starting materials, taken from the Boehringer 1973 patent, makes bioactive TIC10 with a three-fused-ring angular structure (tint), not the linear structure shown in the reaction scheme below and in the patent.

EffRx Pharmaceuticals has received US Food and Drug Administration (FDA) orphan-drug designation for its proprietary metformin-based product, EX404, for treatment of paediatric polycystic ovary syndrome (PCOS).

Also known as Stein-Leventhal syndrome, PCOS is a heterogeneous disorder of chronic anovulation and hyperandrogenism.

The syndrome is believed to occur due to hormonal imbalance caused by increased levels of androgens and insulin in the body.

EffRx Pharmaceuticals chairman and CEO Christer Rosén said the FDA’s orphan drug designation of EX404 is a significant step forward in the clinical development programme.

http://www.pharmaceutical-technology.com/news/newseffrx-pharmaceuticals-receives-fda-orphan-drug-designation-for-ex404-4290237?WT.mc_id=DN_News

heparan sulfate mimetic derived from unfractionated heparin with a molecular weight between 5500 and 6200 Da

Necuparanib

M-402
M-ONC-402
MONC 402

http://www.pharmaceutical-technology.com/news/newsmomenta-pharma-receives-fda-orphan-drug-designation-pancreatic-cancer-drug-4287892

Momenta Pharmaceuticals has received orphan drug designation from the US Food and Drug Administration (FDA) for its necuparanib, a heparan sulfate mimetic indicated for treatment of pancreatic cancer.

Momenta Pharmaceuticals chief medical officer Jim Roach said there is a great need for new medications for patients suffering from pancreatic cancer.

“We are encouraged by the progress of the programme to date, and in the next several months, we anticipate completing Part A of our ongoing Phase I/II study of necuparanib in combination with Abraxane and gemcitabine,” Roach said.

“In the next several months, we anticipate completing Part A of our ongoing Phase I/II study of necuparanib in combination with Abraxane and gemcitabine.”

“We look forward to sharing the results from Part A and advancing the product into the Phase II part of the study in the second half of 2014.”

Necuparanib has recently been adopted as the unique non-proprietary name for M402 by The United States Adopted Names.

The drug is derived from unfractionated heparin. It has been engineered to have significantly reduced anticoagulant activity while preserving the relevant antitumor properties of heparin.

Part A dose escalation component of the Phase I/II trial, which is evaluating necuparanib in combination with Abraxane (nab-paclitaxel) and gemcitabine in advanced metastatic pancreatic cancer patients, is expected to be completed in the next several months.

The company is expected to report the clinical data from Part A in the second half this year. The company also plans to begin Part B of the study by the year-end.

Part B will be a randomised, controlled, proof-of-concept study to assess the antitumor activity of necuparanib in combination with Abraxane plus gemcitabine, versus Abraxane plus gemcitabine alone.

Heparin, a highly sulfated heparin-like glycosaniinoglycan (HLGAG) produced by mast cells and isolated from natural sources, is a widely used clinical anticoagulant. However, the effects of natural, or unfractionated, heparin can be difficult to predict and patients must be monitored closely to prevent over- or under-anticoagulation. Low molecular weight heparins (LMWHs) obtained by various methods of fractionation or depolymerization of polymeric heparin have more predictable pharmacological action as anticoagulants, reduced side effects, sustained antithrombotic activity, and better bioavailability than unfractionated heparin (UFH). Several LMWHs are approved for outpatient treatment of thrombotic conditions.

There is increasing interest in the potential role of antithrombotic agents in the management of cancer patients. Results from several recent clinical trials have suggested a survival advantage for certain types of cancer patients treated with LMWHs (reviewed in Lemoine, 2005, Journal of Clinical Oncology, 23: 2119-20).

http://www.google.fm/patents/EP2207811A1?cl=en

The invention is based, in part, on the development of polysaccharide preparations, e.g., preparations of polysaccharides derived from heparin, that lack substantial anticoagulant activity (e.g., preparations of polysaccharides that have substantially no anticoagulant activity) but retain activity in other non-coagulation mediated biological processes, and methods to produce them. These compounds can have one or more of the following features: 1) an anti-Xa activity and an anti-IIa activity each less than 50 IU/mg, and 2) anti-metastatic, anti-angiogenic, anti-fibrotic and/or anti-inflammatory activity. The polysaccharides disclosed herein can also have structural characteristics that distinguish them from other polysaccharides, (e.g., from commercially available heparins). For example, a polysaccharide preparation provided herein can have one or more of the following characteristics: the preparation has less than 50% glycol split uronic acid residues; the preparation has no more than 3 glycol split uronic acid residues (U_G) per polysaccharide chain; the preparation has greater than 40% U_2SH_NS>6S disaccharide residues; degree of desulfation of the preparation is less than 40%; one or more polysaccharide chains in the preparation have a 4,5-unsaturation of a non-reducing end uronic acid residue; one or more polysaccharide chains in the preparation have a 2,5-anhydromannitol residue at the reducing end; and the weight average molecular weight of the preparation is between 3,500 and 7,000 Da. This disclosure includes preparations having one or more of these properties and characteristics as well as methods of making and using such preparations. The disclosure also features methods of using such preparations.

Accordingly, in a first aspect, the invention features a polysaccharide preparation (e.g., a heparin-derived preparation) having the following characteristics: (a) a weight average chain molecular weight between 3,500 and 7,000 Da; (b) an anti-Xa activity and an anti-IIa activity each less than 50 IU/mg (e.g., an anti-Xa activity less than about 40 IU/mg, 30 IU/mg, 20 IU/mg, 15 IU/mg, or 10 IU/mg and an anti-IIa activity less than about 40 IU/mg, 30 IU/mg, 20 IU/mg, 10 IU/mg, 5 IU/mg, 4 IU/mg, or 3 IU/mg); and (c) less than 50% glycol split uronic acid residues (e.g., less than 40%, 30%, 25%, or 20% glycol split uronic acid residues) in the preparation. In some embodiments, the preparation contains between 5% and 50% glycol split uronic acid residues (e.g., between 5% and 40%, 5% and 30%, 10% and 50%, 10% and 40%, or 10% and 30% glycol split uronic acid residues).

In a second aspect, the invention features a polysaccharide preparation (e.g., a heparin- derived preparation) having the following characteristics: (a) a weight average chain molecular weight between 3,500 and 7,000 Da; (b) an anti-Xa activity and an anti-IIa activity each less than 50 IU/mg (e.g., an anti-Xa activity less than about 40 IU/mg, 30 IU/mg, 20 IU/mg, 15 IU/mg, or 10 IU/mg and an anti-IIa activity less than about 40 IU/mg, 30 IU/mg, 20 IU/mg, 10 IU/mg, 5 IU/mg, 4 IU/mg, or 3 IU/mg); and (c) the polysaccharide chains of the preparation have no more than 3 glycol split uronic acid residues (UQ) per polysaccharide chain (e.g., each polysaccharide chain has no more than 2 or no more than 1 glycol split uronic acid residue (UQ) per polysaccharide chain).

In a third aspect, the invention features a polysaccharide preparation (e.g., a heparin- derived preparation) having the following characteristics: (a) a weight average chain molecular weight between 3,500 and 7,000 Da; (b) an anti-Xa activity and an anti-IIa activity each less than 50 IU/mg (e.g., an anti-Xa activity less than about 40 IU/mg, 30 IU/mg, 20 IU/mg, 15 IU/mg, or 10 IU/mg and an anti-IIa activity less than about 40 IU/mg, 30 IU/mg, 20 IU/mg, 10 IU/mg, 5 IU/mg, 4 IU/mg, or 3 IU/mg); and (c) polysaccharide chains of the preparation have on average no more than 3 glycol split uronic acid residues (Uo) per polysaccharide chain (e.g., on average no more than 2.5, no more than 2, no more than 1.5, or no more than 1 glycol split uronic acid residues (U_G) per polysaccharide chain.

In a fourth aspect, the invention features a polysaccharide preparation (e.g., a heparin- derived preparation) having the following characteristics: (a) a weight average chain molecular weight between 3,500 and 7,000 Da; (b) an anti-Xa activity and an anti-IIa activity each less than 50 IU/mg (e.g., an anti-Xa activity less than about 40 IU/mg, 30 IU/mg, 20 IU/mg, 15 IU/mg, or 10 IU/mg and an anti-IIa activity less than about 40 IU/mg, 30 IU/mg, 20 IU/mg, 10 IU/mg, 5 IU/mg, 4 IU/mg, or 3 IU/mg); and (c) the preparation has greater than 40% U_2SH_NS,6S disaccharide residues (e.g., greater than 50%, 60%, 70%, or 80% U_2SH_NS,6S disaccharide residues). In some embodiments, the preparation has a degree of desulfation less than 40% (e.g., less than 30%, 20%, or 10%).

In a fifth aspect, the invention features a polysaccharide preparation (e.g., a heparin- derived preparation) lacking substantial anticoagulant activity (e.g., having substantially no anticoagulant activity), wherein the preparatiorrmdudes-polv^accharides that include Formula I:

[U_w-H_Xjy)Z]_m~[U_G-H_X5y5Z]_n

wherein U indicates a uronic acid residue and H indicates a hexosamine residue; m and n are integers such that m = 4-16 (e.g., 4-8, 4-9, 4-10, 4-11, 4-12, 4-13, 4-14, or 4-15), and n = 1-4 (e.g., 1-2 or 1-3);

w = -2OS or -2OH; x = -NS or -NAc; y = -3OS or -3OH; z = -60S or -6OH;

wherein the symbol ~ indicates that the units marked m and n are distributed along the polysaccharide chain and are not necessarily in sequence, wherein w, x, y, and z are each the same or different on each unit marked m, and wherein x, y, and z are each the same or different on each unit marked n.

In a sixth aspect, the invention features a polysaccharide preparation (e.g., a heparin- derived preparation) lacking substantial anticoagulant activity (e.g., having substantially noanticoagulant activity) and having antimetastatic activity, wherein the preparation includes polysaccharides that include Formula II:

[U_w-H_Xjy;Z] _m- [U_G-H_X)y;Z] _n- [U_w-H_X;y)Z] ₀- [U_G-H_X^₂] _p- [U_w-H_X;yjZ] _q

wherein U indicates a uronic acid residue and H indicates a hexosamine residue; wherein m-r are integers such that: m = 0-10; n= 0- 3;

O = O-IO;

P = 0-3; q = 0-10;

w = -2OS or -2OH; x = -NS or -NAc; y = -3OS or -3OH; z = -60S or -6OH;

wherein w, x, y, and z are each the same or different on each unit marked m, n, o, p, or q. In some embodiments, the sum of n + p is less than or equal to 4 (e.g., less than or equal to 3, 2, 1, or 0). In some embodiments, the preparation has a weight average chain molecular weight between 3,500 and 7,000 Da.

Examples of such polysaccharide preparations include chains that include the following:

[U_w-H_X;yjZ]_m~[U_G-H_{x y z}]_n

wherein U indicates a uronic acid residue and H indicates a hexosamine residue, wherein m and n are integers such that m = 6-18, and n = 1 -4, w = -2OS or -2OH, x = -NS or -NAc, y = -3OS or -3OH, z = -60S or -6OH,

wherein the symbol ~ indicates that the units marked m and n are distributed along the polysaccharide chain and are not necessarily in sequence, wherein w, x, y, and z are each the same or different on each unit marked m, and wherein x, y, and z are each the same or different on each unit marked n; and

[U_w-H_X)y)Z]_m-[U_G-H_Xiy)Z]_n-[U_w-H_XjyjZ]_o-[U_G-H_X5y)Z]_p-[U_w-H_X!yiZ]_q

wherein U indicates a uronic acid residue and H indicates a hexosamine residue, wherein m-r are integers such that: m = 0-10, n= 0- 3, o = 0-10, p = 0-3, q = 0-10, w = -2OS or -2OH, x = -NS or -NAc, y = -3OS or -3OH, z = -60S or -6OH,

wherein w, x, y, and z are each the same or different on each unit marked m, n, o, p, or q.

Anti-IIa Activity

Polysaccharide preparations are disclosed herein that provide substantially reduced anti- Ha activity, e.g., anti-IIa activity of about 0 to 50 IU/mg, about 0 to 40 IU/mg, about 0 to 30 IU/mg, about 0 to 25 IU/mg, about 0 to 20 IU/mg, about 0 to 10 IU/mg, about 0 to 5 IU/mg, about 5 to 10 IU/mg, about 5 to 15 IU/mg, about 5 to 20 IU/mg. Anti-IIa activity is calculated in International Units of anti- Ha activity per milligram using statistical methods for parallel line assays. The anti-IIa activity levels described herein are measured using the following principle.

Polysaccharide (PS) + ATIII→ [PS • ATIII]

Ha

PS • ATIII→[PS • ATIII • Ha] + Ha (Excess)

Ha (Excess) + Substrate -» Peptide + pNA (measured spectrophotometrically) Anti-factor Ha activity is determined by the sample potentiating effect on antithrombin (ATIII) in the inhibition of thrombin. Thrombin excess can be indirectly spectrophotometrically measured. The anti-factor Ha activity can be measured, e.g., on a Diagnostica Stago analyzer or on an ACL Futura3 Coagulation system, with reagents from Chromogenix (S-2238 substrate, Thrombin (53 nkat/vial), and Antithrombin), or on any equivalent system. Analyzer response is calibrated using the 2nd International Standard for Low Molecular Weight Heparin.

Latin American Active Pharmaceutical Ingredients Industry Catches Up on the US

The market for active pharmaceutical ingredient in the Americas shows a clear north–south divide: 88% percent for the US and Canada, the rest for South and Central American companies. but as the economy in Latin America booms and prosperity growths, these markets are just about to catch up on the US new figures indicate….http://www.process-worldwide.com/management/markets_industries/articles/374702/

Linde-KCA-Dresden built a pilot plant 16 times the size of the laboratory apparatus for Novo Nordisk A/S

The building layouts show different areas for the pilot plant, the utility systems and the technical rooms with hazardous and non-hazardous proof conditions (top). The engineering documents include

The construction of a pilot plant constitutes an important milestone in the development cycle of a new active pharmaceutical ingredient. Pilot plants are used to gain the technological experience needed for the scale-up process and are required for producing sufficient quantities of the active pharmaceutical ingredient for clinical trials and other types of tests. As a result, even these testing facilities must comply with GMP regulations.

http://www.cpp-net.com/pharma/-/article/5829537/15910929/Challenging+task/

BI-836845

Human monoclonal IgG1 lambda antibody against IGF-1 (insulin growth factor-1) and IGF-2

Phase 2 Clinical

Anticancer protein kinase inhibitor; Anticancer monoclonal antibody

WO-2008155387

Boehringer Ingelheim International Gmbh

BI-836845 is a human monoclonal IgG1 lambda antibody against IGF-1 (insulin growth factor-1) and IGF-2 (insulin growth factor-2). Phase II clinical trials are ongoing at Boehringer Ingelheim for the treatment of patients with breast cancer, and phase I clinical trials are ongoing with patients with advanced solid tumors.

Insulin-like growth factor-1 (IGF-1; a 70 amino-acid polypeptide) and insulin-like growth factor-2 (IGF-2; a 67 amino-acid polypeptide) are 7.5-kD soluble factors present in serum that can potently stimulate the growth of many mammalian cells (reviewed by Pollack et al., 2004). Although IGFs can be detectable in a number of tissues the main source of circulating IGFs is the liver which secretes the IGFs and IGF binding proteins (IGFBPs) in response to a complex signaling pathway that is initiated in the pituitary gland and transduced via growth hormone. On secretion into the bloodstream the IGFs form complexes with the IGFBPs which not only protects them from proteolytic degradation in the serum en route to their target tissues but also prevents their association with the IGF receptors. In addition to this endocrine source of IGFs they are also known to be secreted in an autocrine or paracrine manner in target tissues themselves. This is known to occur during normal fetal development where the IGFs play a key role in the growth of tissues, bone and organs. It is also seen in many cancer tissues where there is thought to be paracrine signaling between tumour cells and stromal cells or autocrine IGF production by the tumour cells themselves (reviewed by LeRoith D, 2003).

30 May 2014

MEDIA ALERT

ASCO 2014: Boehringer Ingelheim to present latest oncology research, including overall survival results

• Highly anticipated new overall survival data for Giotrif® (afatinib*) to be presented on June 2nd (3:00 – 6:00 PM, E Hall D2 [Abstract #8004 scheduled for 4:00 - 4:12 PM])
• 7 total abstracts accepted for Giotrif® (afatinib*), nintedanib** and BI 836845**: 1 for oral presentation and 6 posters

The activity of the IGFs is thought to be regulated by a complex and relatively poorly understood interaction involving seven different IGFBPs and other serum proteins. Activation of the IGFs involves their release from this ternary complex after proteolytic release of the serum binding protein and IGFBPs, this is thought to occur in close proximity to cell surfaces where the IGFs are then free to bind to their receptors and transduce intracellular signals that ultimately leads to cellular proliferation and the inhibition of apoptosis. IGF-1 and IGF-2 are able to bind to the IGF-1 receptor (IGF-1R) expressed on many normal tissues, which functionally is a 460 kD heterotetramer consisting of a dimerised alpha- and beta-subunit, with similar affinities (Rubin et al., 1995). IGF-2 can also bind to the IGF-2 receptor (also know as the mannose-6-phosphate receptor) which does not have any known signaling function, rather it is thought to act as a sink for IGF-2 and prevent it from binding and signaling through the IGF-1R. In this respect the IGF-2R has been demonstrated to be a tumour suppressor protein. The IGF-1R is structurally similar to the insulin receptor which exists in two forms, IR-A and IR-B, which differ by an alternatively spliced 12 amino acid exon deletion in the extracellular domain of IR-A. IR-B is the predominant IR isoform expressed in most normal adult tissues where it acts to mediate the effects of insulin on metabolism. IR-A on the other hand is known to be highly expressed in developing fetal tissues but not in adult normal tissues. Recent studies have also shown that IR-A, but not IR-B, is highly expressed in some cancers. The exon deletion in IR-A has no impact on insulin binding but does cause a small conformational change that allows IGF-2 to bind with much higher affinity than for IR-B (Frasca et al., 1999; Pandini et al., 2002). Thus, because of it’s expression in cancer tissues and increase propensity for IGF-2 binding, IR-A may be as important as IGF1-R in mediating the mitogenic effects of IGF-2 in cancer.

Binding of the IGFs to IGF-1R triggers a complex intracellular signaling cascade which results in activation of proteins that stimulate growth and inhibit apoptosis (reviewed by Pollack et al., 2004). In terms of growth, upregulated translation is induced by the activation of p70 S6 kinase, which in turn phosphorylates the S6 ribosomal protein (Dufner and Thomas, 1999). Thus, IGF-stimulated cell growth can be measured by the rapid increase in phosphorylated S6 ribosomal protein.

Unlike the EGFR and Her2neu receptors there is no known amplification of the IGF1-R or IR-A receptors in cancers indicating that receptor activation is controlled by the presence of active ligand. There is a very large body of scientific, epidemiological and clinical literature implicating a role for the IGFs in the development, progression and metastasis of many different cancer types (reviewed by Jerome et al., 2003; and Pollack et al., 2004).

For example, in colorectal cancer the expression of IGF-2 mRNA and protein is elevated in clinical colorectal tumour specimens compared with adjacent normal tissue (Freier et al., 1999; Li et al., 2004). There is also a positive correlation of elevated IGF serum levels with proliferating cell index in patients with colorectal neoplasia (Zhao et al., 2005). In addition, elevated circulating levels of IGF-2 correlate with an increased risk of developing colorectal cancers and adenomas (Renehan et al., 2000a) and b); Hassan et al., 2000). Loss of parental imprinting (LOI) of the IGF-2 gene, an epigenetic alteration that results in elevated IGF-2 expression, is a heritable molecular trait that has recently been identified in patients with colorectal and other tumour types. Loss of IGF-2 imprinting has been shown to be associated with a five-fold risk of colorectal neoplasia (Cui et al., 2003; Cruz-Correa et al., 2004) and adenomas (Woodson et al., 2004). Antibodies targeting the alpha-subunit of the IGF-1R which block IGF binding and internalize the receptor have been shown to delay the growth of the xenografted colon cancer-derived cell lines such as COLO 205 (Burtrum et al., 2003).

Elevated levels of IGFs are associated with a poor prognosis in human pulmonary adenocarcinomas (Takanami et al., 1996) and IGFs are expressed and secreted by many SCLC— and NSCLC-derived cell lines (Quinn et al., 1996). Transgenic over-expression of IGF-2 induces spontaneous lung tumours in a murine model (Moorhead et al., 2003). In terms of hepatocellular carcinoma (HCC), human clinical specimens and animal models of HCC express higher levels of IGF mRNA and protein than corresponding normal tissues and this has been correlated with increased tumour growth (Wang et al., 2003; Ng et al., 1998). IGF-2 has also been shown to be a serological marker of HCC with elevated levels in the serum of HCC patients compared with controls (Tsai et al., 2005). An orthotopic xenograft tumour model of HCC was established using Hep 3B cells, and used to demonstrate that inhibition of IGF-2 expression using a methylated oligonucleotide enhances survival (Yao et al., 2003a) and b).

Many childhood solid tumours such as Ewing sarcoma and rhabdomyosarcoma appear to be particularly dependent on the IGF signaling pathway for their growth (Scotlandi et al., 1996). LOI of the IGF-2 gene has been implicated as a primary genetic event in the development for embryonal rhabdomyosarcoma (Fukuzawa et al., 1999). Autocrine IGF signaling is also thought to strongly influence the growth of Ewing sarcoma in cases where the type-1 EWS-FLI1 chimeric transcription factor is expressed through a chromosomal translocation resulting in elevated expression of target genes including the IGF ligands and IGF-1R, and reduced expression of IGFBP-3. Antibodies and small molecule compounds targeting the IGF-1R have been shown to reduce the growth of xenografted pediatric solid tumour derived cell lines (Kolb et al., 2008; Manara et al., 2007).

Using IGF ligand-specific antibodies it has been demonstrated that the growth of human prostate cancer cells in adult human bone implanted into SCID mice can be inhibited (Goya et al., 2004). In addition, it was demonstrated that the same IGF ligand antibodies could block the paracrine supply of IGF and suppress the liver metastasis of human colorectal cancer cells in a murine xenograft system (Miyamoto et al., 2005).

There is also considerable evidence suggesting that the IGF signaling system reduces the sensitivity of cancers to chemotherapeutic agents and radiation. One of the earliest findings in this respect was the demonstration that IGF-1R knock-out mouse embryos are refractory to transformation by viruses, oncogenes and over-expressed growth factor receptors (Sell et al., 1993; Sell et al., 1994) and that over-expression of IGF-1R protects cells from UV irradiation and gamma radiation-induced apoptosis (Kulik et al., 1997). Furthermore, using liver tumour cell lines that secrete large amounts of IGF-2, it was found that neutralization of IGF-2 significantly increased response to chemotherapeutic agents such as cisplatin and etoposide in vitro, especially at lower, cytostatic doses, suggesting that IGF-2 can reduce the susceptibility to chemotherapeutic agents (Lund et al., 2004). Consistent with these findings it has been demonstrated that antibodies targeting the IGF-1R increase the susceptibility of tumour xenografts to growth inhibition by chemotherapeutic drugs and radiation (Goetsch et al., 2005).

A number of antibodies that show cross-reactive binding to human IGF-1 and human IGF-2 have been reported. Antibody sm1. was raised against human IGF-1 and shows 40% cross-reactivity to human IGF-2 and was shown to inhibit the proliferation of a mouse fibroblast cell line BALB/c3T3 which was stimulated with 20 ng/ml human IGF-1 (Russell et al., 1984). In a study designed to functionally epitope map IGF-1 by raising monoclonal antibodies to whole IGF-1 protein and portions of the protein a number of antibodies where identified that cross reacted with IGF-2 (Manes et al., 1997). The percent cross-reactivity with IGF-2 ranged from 0 to 800% and several antibodies were identified which were equally IGF-1 and IGF-2 reactive. KM1486 is a rat monoclonal antibody that cross-reacts with human IGF-1 and IGF-2 and it was demonstrated that KM1486 can inhibit growth of human prostate cancer cells in human adult bone implanted into nonobese diabetic/severe combined immunodeficient mice (Goya et al., 2004). In addition, it was demonstrated that KM1486 suppresses the liver metastasis of human colorectal cancers (Miyamoto et al., 2005). KM1486 has also been described in WO 03/093317, JP 2003-310275, WO 2005/018671, WO 2005/028515, and WO 2005/027970.

For the treatment of human disease an antibody with a fully human sequence is highly desirable in order to minimize the risk of generating a human anti-antibody reaction and neutralizing antibodies that will rapidly eliminate the administered antibody from the body and thereby reduce the therapeutic effect. As such, and given the roles of IGF-1 and IGF-2 dependent signaling in the development and progression of cancers it would be desirable to obtain high affinity fully human antibodies that co-neutralise the mitogenic effects of both ligands.

In addition, to maximize the therapeutic potential of such an antibody, it is important to have a suitably long terminal half life (T_1/2). Prior to terminal half life determination in human subjects, the most accurate estimation of an antibody’s human terminal half life can be obtained from administration to non-human primates such as cynomolgus monkeys. For example, bevacizumab, a registered humanized monoclonal antibody against vascular endothelial growth factor (VEGF) used for the treatment of several human cancers, has a terminal half-life in cynomolgus monkeys of 8.57±0.38 days (Lin et al., 1999), which translates to a terminal half life in humans of approximately 20 days allowing for a single administration once every two weeks (Lu et al., 2008).

It was a further object of the invention to obtain an antibody that does not affect binding of insulin to its receptor.

The clinical development of therapeutic agents is supported by pharmacodynamic biomarkers of drug activity. Clinical studies with antibodies targeting the IGF-1R have demonstrated that an increase in total serum IGF-1 levels may be a useful pharmacodynamic marker for these agents (Pollack et al., 2007). The reason for the increase in total serum IGF-1 levels is likely due to a feedback mechanism involving pituitary growth hormone (GH) secretion which releases both IGF-1 and IGFBPs from the liver. Indeed, in humans it has been demonstrated that free or bioactive IGF-1, which represents only around 1% of total IGF-1 levels, determines the feedback response (Chen et al., 2005). The inventors thus sought to confirm whether total serum IGF-1 levels are also a useful pharmacodynamic marker for the activity of a therapeutic anti-IGF antibody. In this case it would be desirable for such antibody to be cross-reactive with IGFs from a suitable animal species, e.g. mouse or rat, such that a pharmacodynamic effect can already be tested pre-clinically.

Boehringer Ingelheim
The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, Boehringer Ingelheim operates globally with 142 affiliates and a total of more than 47,400 employees. The focus of the family-owned company, founded in 1885, is researching, developing, manufacturing and marketing new medications of high therapeutic value for human and veterinary medicine.

Taking social responsibility is an important element of the corporate culture at Boehringer Ingelheim. This includes worldwide involvement in social projects, such as the initiative “Making more Health” and caring for the employees. Respect, equal opportunities and reconciling career and family form the foundation of the mutual cooperation. In everything it does, the company focuses on environmental protection and sustainability.

In 2013, Boehringer Ingelheim achieved net sales of about 14.1 billion euros. R&D expenditure corresponds to 19.5% of its net sales.

Fig.1 Production of MAb

Adam, P.J.; Ostermann, E.; Lamche, H.R.; Hofmann, M.H.; Kroez, M.; Borges, E.; Adolf, G.R.
Pharmacodynamic properties and anti-tumor efficacy of BI 836845, a fully human IGF ligand neutralizing antibody
AACR-NCI-EORTC Int Conf Mol Targets Cancer Ther (November 12-16, San Francisco) 2011, Abst A208

Epirus Switzerland GmbH, a subsidiary of Boston-based Epirus Biopharmaceuticals focused on the global development and commercialization of biosimilar monoclonal antibodies, announced clinical data from a Phase 3 study of the efficacy and safety of BOW015, a biosimilar infliximab, in patients with active rheumatoid arthritis (RA).

Phase 3 data demonstrate comparability of Epirus’ BOW015 to Remicade for rheumatoid arthritis:

Epirus Switzerland GmbH, a subsidiary of Boston-based Epirus Biopharmaceuticals focused on the global development and commercialization of biosimilar monoclonal antibodies, announced clinical data from a Phase 3 study of the efficacy and safety of BOW015… READ MORE