Invented by Peter Ellmark, Sara Fritzell, Christina Furebring, Jessica Petersson, Anna Sall, Karin Enell Smith, Laura Varas, Laura Von Schantz, Niina Veitonmaki, Alligator Bioscience AB

The Market for Anti-CD137 Antibodies and Their Uses In recent years, the field of immunotherapy has gained significant attention for its potential in revolutionizing cancer treatment. One promising avenue in this field is the use of immune checkpoint inhibitors, which are designed to enhance the body’s immune response against cancer cells. Among these inhibitors, anti-CD137 antibodies have emerged as a promising therapeutic option, leading to a growing market demand. CD137, also known as 4-1BB, is a protein receptor found on the surface of immune cells, particularly T cells. When activated by binding to its ligand, CD137 plays a crucial role in stimulating T cell proliferation, survival, and effector functions. By targeting CD137, anti-CD137 antibodies can enhance the immune response against cancer cells, leading to improved tumor control. The market for anti-CD137 antibodies is primarily driven by the increasing prevalence of cancer worldwide. According to the World Health Organization (WHO), cancer is one of the leading causes of death globally, with approximately 10 million deaths reported in 2020 alone. This alarming statistic has created a pressing need for effective and targeted cancer therapies, leading to a surge in research and development activities in the field of immunotherapy. Several pharmaceutical companies are actively engaged in the development of anti-CD137 antibodies, contributing to the growth of this market. These companies are investing significant resources in clinical trials to evaluate the safety and efficacy of their antibody candidates. The results from these trials have been promising, with some studies demonstrating improved overall survival rates and durable responses in patients with various types of cancer. The potential applications of anti-CD137 antibodies extend beyond cancer treatment. Preclinical studies have shown their efficacy in treating autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis. By modulating the immune response, anti-CD137 antibodies have the potential to restore immune homeostasis and alleviate disease symptoms. This widening scope of applications further contributes to the market growth of anti-CD137 antibodies. However, challenges remain in the development and commercialization of anti-CD137 antibodies. One major hurdle is the potential for immune-related adverse events, which can occur due to the overstimulation of the immune system. These adverse events range from mild to severe, requiring careful monitoring and management during treatment. Additionally, the high cost of antibody production and the need for specialized manufacturing facilities pose logistical challenges for companies entering this market. Despite these challenges, the market for anti-CD137 antibodies is projected to witness substantial growth in the coming years. The increasing understanding of the immune system and its role in cancer progression, coupled with advancements in antibody engineering and manufacturing technologies, will drive the development of more potent and safer anti-CD137 antibodies. In conclusion, the market for anti-CD137 antibodies is expanding rapidly, driven by the growing demand for effective cancer therapies and the potential applications in autoimmune diseases. With ongoing research and development efforts, these antibodies hold great promise in improving patient outcomes and revolutionizing the field of immunotherapy. However, addressing the challenges associated with immune-related adverse events and manufacturing costs will be crucial for the successful commercialization of anti-CD137 antibodies.

The Alligator Bioscience AB invention works as follows

The present invention is a set of antibodies (and variants, fusions, derivatives, and fragments thereof) that bind to domain 2 of the human CD137, which can inhibit the binding of reference antibodies to human CD137. These antibodies and fragments are useful in treating diseases like cancer. “The invention also relates pharmaceutical compositions, methods, and kits containing such antibodies.

Background for Anti-CD137 antibodies, and their uses

CD137 (4-1BB) is a TNF (TNFRSF9) superfamily member that is expressed by activated CD4+, CD8+ T-cells, Tregs, DCs, monocytes and mast cells. CD137 activation is important for CD8+ T-cell activation and survival. (Lee, 2002; Pulle, 2006). It maintains and augments effector functions, but does not initiate them (Shuford and colleagues, 1997). CD137 stimulation in CD4+ T-cells initially causes activation, and then activation-induced death. This explains why CD137 antagonistic antibodies show therapeutic effects in autoimmunity as well as tumour immunity (Zhang, JCI, 2007, Sun, Current Mol Med, 2003). CD137 suppresses Treg activity (So, Cytokine growth factor Rev, 2008). “Activation of CD137 depends on receptor oligomerization” (Rabu, 2005; Wyzgol, 2009).

The CD137 agonistic antibodies have been shown to activate tumour endothelial cell, resulting in upregulation of ICAM-1, VCAM-1, and improved T-cell recruitment (Palazon Cancer Res, 2011, 2011).

Melero CCR 19 (5)1044-53, 2013, and the references therein, state that “CD137 is upregulated in NK cells activated either by cytokines, or CD16” (see Melero). CD137 activates NK cells both in mice and in humans, potentiating ADCC. (Kohrt et. al., 2014.) However, there are reports that suggest opposite effects in mice and in humans.

Several studies have demonstrated induction of tumour immunity by treatment with agonistic CD137 antibody (Dubrot et al., 2010; Gauttier et al., 2014; Kim et al., 2001; McMillin et al., 2006; Melero et al., 1997; Miller et al., 2002; Sallin et al., 2014; Taraban et al., 2002; Uno et al., 2006; Vinay and Kwon, 2012; Wilcox et al., 2002). In addition, it synergizes with several immunomodulators, including CpG, TRAIL, CD40, OX-40, DRS, PD-1/PD-L1, CTLA-4 Tim-3, IL-2, IL-12 (Curran et al., 2011; Gray et al., 2008; Guo et al., 2013; Kwong et al., 2013; Lee et al., 2004; Morales-Kastresana et al., 2013; Pan et al., 2002; St Rose et al., 2013; Uno et al., 2006; Wei et al., 2013; Westwood et al., 2010; Westwood et al., 2014a; Westwood et al., 2014b) in pre-clinical models.

Two CD137 antibodies are currently in clinical trials. Urelumab is a human IgG4 fully antibody that was developed by Bristol-Myers Squibb. There are several phase I and Phase II studies being conducted in different indications. Pfizer is developing PF-05082566, a human IgG2 fully antibody. The drug is in phase 1 development for lymphoma, and other solid cancers.

The agonistic effect of CD137 antibodies is affected by the isotype of the Fc region. The antibodies tested in the clinic are either IgG2 or IgG4. Like most TNFR family members, CD137 depends on cross linking for activation (Wilson 2011, Cancer Cell). The CD137L expressed on the membrane of an APC may induce significant multiple cross linking of the receptor. An antibody can by itself only cross link two CD137 receptors, and to induce a strong signal, further cross linking via Fc?Rs expressed on other cells (in trans) may be necessary for induction of a strong CD137 mediated signal. An exception to this may be IgG2 antibodies, which induce a cross linking independent signaling by an unknown mechanism (White et al, 2015 Cancer Cell). T cells do not express Fc?Rs, and the Fc?R mediated cross linking in vivo is thought to be mediated by monocytes, macrophages, DCs and potentially B cells and other cell types. It has been suggested that interaction with the inhibitory Fc?R Fc?RIIB plays a major role for this effect in mouse models for CD40 agonists (Li 2011, Science), whereas for OX40 antibodies, interactions with activating receptors may be of greater importance (Bulliard 2014, Imm and Cell Biol). For CD137 antibodies, Fc?RII is not critical (Sanmamed 2015, Semin Onc). The translational relevance of this is uncertain, since the human Fc?R distribution as well as the affinity of different IgG isotypes to different Fc?R differs from mice. Further, human IgG1 binds to mFc?RIIb with relatively low affinity, similar to mIgGIIa and considerably lower than mIgG1, the latter having the most potent effect in vivo (Li Science 2011, Overdijk 2012 JI, Horton et al 2008, White et al 2011 and 2014).

Another thing to consider is that the engagement of Fc-R receptors can also cause ADCC, antibody dependent cellular phagocytosis and complement-dependent cytotoxicity on cells coated by antibodies (for ease ADCC includes ADCP and CDC). Human IgG1 can be a powerful inducer of NK/Macrophage-dependent ADCC depending on the type of target, cell type, and receptor density. IgG4 may induce ADCC, but at a lesser extent than IgG1 antibodies (Wang 2015 Front Imm; Vidarson 2014. Front Imm).

The effect of a CD137-agonistic antibody of different isotypes will be affected by the balance of 1) inducing ADCC which can lead to the killing of Tregs and effector T cells, primarily CD8 T cell. The net effect from 1) and 2) is likely to depend on the distribution and number of CD137-expressing cells, whether the target cells can engage with immune cells expressing Fc?R, the receptor density, affinity, and the sensitivity to ADCC of Tregs vs Teff. In melanoma tumors, CD137 is expressed on both CD8 and Tregs (Quezada presentation SITC 2015). The IgG4 form would allow Fc?RI mediated binding by macrophages, monocytes and NK cells while minimizing NK mediated ADCC to effector CD8 T-cells.

As outlined above, due to the differences in expression and affinity of murine and human FcRs, it can be difficult to compare different human Fcs in mouse models. The functional consequences of antibodies that block the binding of CD137L and CD137 in vivo are currently being debated.

Several studies have demonstrated induction of tumour immunity by treatment with agonistic CD137 mAb (Dubrot et al., 2010; Gauttier et al., 2014; Kim et al., 2001; McMillin et al., 2006; Melero et al., 1997; Miller et al., 2002; Sallin et al., 2014; Taraban et al., 2002; Uno et al., 2006; Vinay and Kwon, 2012; Wilcox et al., 2002). In vivo studies on mice are often conducted using two different antibodies, Lob12.3 or 3H3(Shuford 1997 Journal of Exp. Medicine).

The toxicity observed in mouse models was detected after repeated dosing, in a dose-dependent but not time-dependent manner (Ascierto 2010, Semin Onc; Dubrot 2010, Can Imm; Niu 2007, JI). This toxicity is a combination of skin toxicity, liver toxicity (aspartate amino transase/alanine amino transferase ratio ASAT/ALAT), and cytokine production. This indicates that the toxicity is either mediated by CD137, which pre-activates immune cell populations (likely a T-cell population), or that it is caused by secondary effects from antidrug antibodies (ADA), which may form aggregations that lead to increased cross-linking. The toxicities in mice can be reversed and seem to be dependent on the TNFa/CD8 cells (Ascierto 2010, Sem Onc). The toxicology studies on monkeys revealed that both a single dose of 100 mg/kg or repeated doses once weekly over four weeks were tolerable. No skin or liver toxicity was detected.

Continuous and prolonged activation via TNF receptors may lead to immune fatigue.” It may be advantageous to administer these antibodies in a way that allows resting periods for cells expressing receptors. To increase the resting time in a particular dosing regimen, one approach is to decrease the half-life by decreasing the antibody’s binding to the neonatal FcRn. This could also, depending on how the treatment is administered, reduce the toxic effects of the treatment.

There is still a need for better anti-tumour treatments, notably anti-CD137 antibody suitable for clinical use, with improved properties such as reduced toxicities.

A first aspect provides an antigen-binding polypeptide or antibody (?antibody polypeptides?) “A first aspect of the invention provides an antibody or an antigen-binding fraction thereof (?antibody polypeptides?) “A CD137 agonist is an antibody or antigen-binding fragment that binds to domain 2 of human CD137 and inhibits the binding of reference antibody?1630/1631?

The second aspect of the invention provides an antibody (or an antigen-binding polypeptide) or an antibody-binding fragment. “A second aspect of the invention provides an antibody or an antigen-binding fraction thereof (?antibody polypeptides?) “A CD137 agonist is an antibody or antigen-binding fragment that binds to domain 2 of human CD137 and inhibits the binding of reference antibody?2674/2675?

In one embodiment, the antigen-binding fragment or antibody is capable of blocking the binding of the reference antibody. and/or ?2674/2675? “Human CD137

The first aspect of this invention provides antibody polypeptides that are capable of blocking the binding of one of more reference antibodies to CD137 in humans.

The following disclosures can be applied to the first and second aspects of the invention.

By ?CD137? “By?CD137?, we include specifically the human CD137 proteins as described in GenBank Accession No. AAH06196.1, whose sequence is shown in SEQ ID No: 11 below. In the scientific literature, CD137 is known as 4-1BB or TNFRSF9.

Human CD137, amino acid sequence: >gi|571321|gb|AAA53133.1| 4-1BB [Homo sapiens]

[SEQ ID NO: 11]\nMGNSCYNIVATLLLVLNFERTRSLQDPCSNCPAGTFCDNNRNQICSPCPP\nNSFSSAGGQRTCDIC RQCKGVFRTRKECSSTSNAECDCTPGFHCLGAGCS\nMCEQDCK QGQELTKKGCKDCCFGTFNDQKRGICRPWTNCSLDGKSVLVNG\nTKERDVVCGPSPADLSPGASSVTPPAPAREPGHSPQIISFFLALTSTALL\nFLLFFLTLRFSVVKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEE\nGGCEL

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