Therapeutic Monoclonal Antibodies

Therapeutic antibodies are developed for the treatment of human diseases. Their therapeutic function is proven in clinical trials and they are registered with the medical regulatory authority such as EMA or FDA

Aliquots of Monoclonal
Antibody Drugs

Drug Aliquots

Therapeutic antibody drugs are purchased by Evidentic from the original drug manufacturers. These drugs are Not further modified or processed but repackaged (aliquoted) into smaller volumes, called ‘drug aliquots’. They are in their clinical use buffer and concentration (5-150mg/ml)

Aliquoted

Diluted with PBS

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Therapeutic antibody
@1mg/ml in PBS

Therapeutic antibody drugs are purchased by Evidentic from the original drug manufacturers. These drugs are then diluted in PBS to obtain a therapeutic antibody at 1mg/ml

List of EMA/FDA approved therapeutic antibodies available at Evidentic

Therapeutic antibodyBrand nameTarget
Adalimumab therapeutic antibodyHumira®TNF-α
Aflibercept therapeutic antibodyEylea®VEGF-A
Atezolizumab therapeutic antibodyTecentriq®PD-L1
Avelumab therapeutic antibodyBavencio®PD-L1
Bevacizumab therapeutic antibodyAvastin®VEGF-A
Cetuximab therapeutic antibodyErbitux®EGFR
Daratumumab therapeutic antibodyDarzalex®CD38
Denosumab therapeutic antibodyProlia®RANKL
Durvalumab therapeutic antibodyImfinzi®PD-L1
Etanercept therapeutic antibodyEnbrel®TNF-α
Golimumab therapeutic antibodySimponi®TNF-α
Guselkumab therapeutic antibodyTremfya®IL23
Infliximab therapeutic antibodyRemicade®TNF-α
Ipilimumab therapeutic antibodyYervoy®CD152/CTLA4
Nivolumab therapeutic antibodyOpdivo®PD-1
Obinutuzumab therapeutic antibodyGazyvaro®CD20
Palivizumab therapeutic antibodySynagis®RSV proteinF
Pembrolizumab therapeutic antibodyKeytruda®PD-1
Pertuzumab therapeutic antibodyPerjeta®HER2
Ramucirumab therapeutic antibodyCyramza®VEGFR2
Ranibizumab therapeutic antibodyLucentis®VEGF-A
Risankizumab therapeutic antibodySkyrizi®IL23
Rituximab therapeutic antibodyMabthera®CD20
Secukinumab therapeutic antibodyCosentyx®IL17A
Tocilizumab therapeutic antibodyRoActemra®IL-6R
Trastuzumab therapeutic antibodyHerceptin®HER2
Ustekinumab therapeutic antibodyStelara®IL-12

Therapeutic antibodies

Antibodies are important components of the immune system that confer specific immunity. The specific targeting ability of antibodies has been exploited in research and medical diagnosis since decades. The revolutionary hybridoma technology, developed by Köhler and Milstein in 1975, made it possible to produce monoclonal antibodies (mAbs) in a large scale. This paved way for the translation of mAbs as a therapeutic modality with the first therapeutic mAb, the CD3-specific muromonab (OKT3), coming into existence in 1986. Therapeutic antibodies are now an important class of drugs that have applications in various therapeutic areas including cancer, inflammatory disease, organ transplantation, cardiovascular disease, pathogenic infection, respiratory disease and ophthalmological disease.

So far, nearly 79 mAb drugs have been approved for clinical use and more than 500 are in the clinical development pipeline. Therapeutic intervention using antibodies have been very successful, particularly in cancer and inflammatory diseases, which were previously considered as very difficult to treat.

Different generations of therapeutic antibodies

Ever since the first mAb drug, antibody engineering technologies have drastically evolved. Each successive generation of mAb therapeutics was intended to enhance the clinical benefits and minimize toxicities. The main areas of focus in therapeutic mAb design are high target specificity, better systemic retention, and low immunogenicity. The following are the different generations of antibodies that have made an impact.

  • Murine Antibodies (suffix – “momab”)

    The murine antibodies were the first antibodies to be developed at lab scale using the hybridoma technology in rodents. But because of the differences between the human and rodent immune system, usage of murine antibodies resulted in cytotoxicity. Thus their continuous administration often resulted in allergic reactions and anaphylactic shock, termed as human anti-mouse or anti-murine antibody (HAMA) response. Anti-CD3 mAb of murine origin (OKT-3), the first therapeutic mAb, approved for treatment of transplantation rejection was discontinued primarily due to severe HAMA response in patients. Nevertheless, murine antibodies serve as frameworks for antibody development. Also due to the improved and optimized protocols for antibody generation from hybridoma mouse cell lines, this technology is considered popular and economical to produce new antibodies.

  • Chimeric MAbs (suffix – “ximab”)

    In order to minimize the HAMA response, chimeric antibodies were manufactured. These antibodies consist of 65% human genetic component by recombination of human constant regions and mouse variable regions in a suitable expression system. There are some chimeric antibodies approved by the FDA for use in human therapy and research, for eg., Infliximab, Rituximab, Abciximab. Presently even though there is a declining interest in developing chimeric antibodies for clinical applications, chimeric molecules can be widely used in the initial stage of antibody humanization strategies and also serve as controls and calibrators for specific research needs or in diagnostics applications.

  • Humanised MAbs (suffix – “zumab”)

    The urgency to overcome the obstacles presented by low complementarity of the mouse line developed antibodies to the patient’s immune system, gave way to the creation of humanized antibodies. The humanized antibodies are close to 95% in human origin, with only the complementarity determining regions (CDRs) of the variable regions having mouse-sequence origin. However, these Abs sometimes present lower affinity than the parent murine mAbs with respect to binding with antigens. So as to increase the antibody-antigen binding affinity, techniques such as chain-shuffling randomization can be employed to introduce some transformations into the CDR. Daclizumab is the first FDA-approved humanized antibody, used in the treatment of multiple sclerosis.

  • Fully human MAbs (suffix – “mumab”)

    Fully human sequence derived antibodies have no murine sequence, and are largely produced via two sources: phage display technologies and transgenic mice. The first fully human sequence-derived antibody to be approved for therapeutic use was adalimumab (Humira), a fully human IgG1 antibody specific for TNFalpha that was selected via phage display of human VH and VL sequences.

The two main technology platforms that are currently used for manufacturing fully human mAbs are:

  • Phage display technology

This method is used to produce diverse libraries of phage displayed antibody variable regions (scFv or Fab) thus providing quick access of target specific mAbs, without creating a library of hybrid clones. Through biopanning, an in-vitro screening technique using specific antigens, the phages expressing antibody fragments exhibiting better affinities are identified, sequenced and used for development of fully human mAbs.

  • Transgenic mice

Transchromosomal engineering process has aided the introduction of transgenes encrypting human immunoglobulin heavy and light chains, into mice germline. This has led to successful development of mAb drugs from human-antibody producing mouse. Some of the advantages of this technology include direct generation of full-length IgG, more diversity and in-vivo affinity maturation. However, this method is not preferred for toxic antigens.

Novel therapeutic antibody structures

Technical advancement in biochemistry and antibody engineering has brought about new platforms for therapeutic antibody development. Some of these engineered Ab formats that are currently in clinical use are discussed below

  • Bispecific antibodies (BsAb)

BsAbs are artificially engineered mAbs that can bind to two epitopes. They can be a cost-effective alternative to combination therapy by targeting two different signaling pathways. The approach can also be used to effectively bind to a target cell and an immune cell to induce cytotoxic signaling. The currently approved BsAb formats are the full-length IgG-like asymmetric antibody and the single-chain variable fragment (scFv)-based Ab with no Fc fragment. Several other BsAb formats are under development and some in clinical evaluation phase.

  • Antibody-drug conjugates (ADC)

ADCs are an effective method to broaden the therapeutic window of primary Abs. The mAb can be conjugated to a cytotoxin drug or radioactive element via a non-cleavable linker. This approach increases therapeutic potency hence low doses can suffice the required clinical efficacy.

Mechanisms of action of therapeutic antibodies

Therapeutic antibodies are usually homogenous preparations of monoclonal IgG1 monomers with identical protein sequences in order to ensure the desired biological effect in a consistent manner. In addition to specific receptor targeting and longer half-life in blood, the IgG class of antibodies exhibit effector functions that is now being tapped as a major therapeutic mode of action for clinical efficacy. Some of the key mechanisms of action (MoAs) exploited in antibody therapeutics are described here

  • Signaling blockade

    The antibody can bind to the receptor on the target cell in an antagonistic fashion. The mAb can inhibit an undesired signaling pathway by blocking ligand-binding or interfering with the di/trimerization process to bring about the preferred physiological effect. For example, the mAb-ligand binding can give rise to inhibition of proliferative signals, blockade of immune checkpoints, induction of pro-apoptotic programs or re-sensitization of cell to a cytotoxic agent. Bispecific antibodies can target two ligands simultaneously so as to block redundant pathways.

  • Fc-domain mediated activation

    Fc mediated response occurs when the target cell is opsonized with the several mAb drug molecules. The Fc region can bind to various molecules eliciting a cytotoxic response which can be via

    (i) Antibody-dependent cell-mediated cytotoxicity (ADCC) – The Fc domain can bind to FcγRIIIA on NK cells triggering cell destruction via lytic factors secreted by the NK cells.

    (ii) Complement‐dependent cytotoxicity (CDC) – The C1q subunit of the C1 compliment factor binds to the Fc domain initiating a signalling cascade that finally leads to the formation of a membrane attack complex (MAC), a pore that causes cell lysis.

    (iii) Antibody-dependent cellular phagocytosis (ADCP or ADPh) – FcγRI expressed on macrophages, neutrophils, and eosinophils can bind to the Fc domain resulting in phagocytosis.

  • Agonist antibodies

    Here, the mAb-receptor binding activates a desired cellular pathway which is, in most cases, the activation of immune cells. Agonism of co-stimulatory ligands on T-cells and dendritic cells are currently being explored as an anti-cancer therapeutic strategy.

  • Receptor-mediated antibody internalization

    It is the main moA utilized by ADCs. Binding of the ADC to the target cell leads to endocytosis of the mAb complex, enabling intracellular delivery of the drug resulting in cell death. Certain payloads have the ability to diffuse and kill surrounding cells, a phenomenon termed as “bystander killing” which is useful in the case of solid tumors.

Most of the therapeutic antibodies elicit more than one of these pharmacological actions. Therefore, while developing mAb therapeutics, it is crucial to thoroughly evaluate the biological activity in-vitro and in in-vivo models using appropriate reference mAbs.

Monoclonal Antibody Therapy

Monoclonal antibody therapies have elevated precision medicine by enabling targeted therapy and providing personalized treatment options. A better understanding of the underlying molecular pathologies in various diseases has helped identify specific therapeutic targets for the development of monoclonal antibody (mAb) drugs. Hence, several mAb drug development also requires the co-development of molecular biomarker-based diagnostics in order to select patients who are most likely to respond.
In the last few years, there has seen an increase in the approval of antibody drugs for clinical use, mainly for cancer and auto-immune diseases. Many more are under clinical evaluation anticipating approval in the coming years. Below we discuss the disease areas where antibody therapies have demonstrated significant success.

Monoclonal Antibody Therapy for Cancer

Monoclonal antibody therapy is one of the most successful treatment strategies for cancer. Over the last two decades, several landmark drugs have been proven efficient, paving way for personalized medicine and biomarker derived treatments.

Cancer treatments using mAb drugs is achieved via various modes of action. Targeted therapy which utilizes mAbs for direct targeting of cancer cells and induction of apoptosis has been one of the most preferred therapeutic strategies. These antibody drugs can specifically bind to cells expressing tumor-specific antigens such as HER2 (Trastuzumab or Herceptin®) and CD52 (Alemtuzumab, trade name Lemtrada®), inhibit cell proliferation signaling pathways and recruit natural killer cells or complement factors. Alternatively, mAbs can be designed to target vascular and stromal components such as VEGF, VEGFR and FAP, in order to slow down tumorigenesis. For example, Bevacizumab, trade name Avastin® (anti-VEGF) can inhibit the growth of blood vessels around the tumor, thereby disrupting the tumor micro-environment and nutrient supply.

Recently, immunotherapy has emerged as a new vertical in cancer treatment after growing evidence demonstrating the immunosuppressive ability of cancer cells. Antibodies targeting immune checkpoint pathways and enabling T-cell activation, known as immune checkpoint inhibitors, have demonstrated considerable success against liquid and solid tumors in clinical trials. Ipilimumab/Yervoy® (anti-CTLA4), Nivolumab/Opdivo® (anti-PD1), and Pembrolizumab/Keytruda® (anti-PD1) are some of the first generations of approved checkpoint inhibitors.

Currently several mAbs have been approved for therapy in cancer and many are in the clinical pipeline. The future of mAb therapeutics aims at personalized combination therapies to overcome tumor heterogeneity and improve treatment efficiency.

Monoclonal Antibody Therapy for Autoimmune Diseases

Autoimmune diseases are generally characterized by inflammation caused by defective elimination or regulation of self-reactive immune cells. This inflammation results in tissue injury and clinical manifestation of the disease. MAbs have revolutionized the treatment of autoimmune diseases as these can target different elements of the immune system to suppress the unrestrained responses. The mode of action of mAbs against autoimmune diseases includes blockade and depletion of T cells and/or B cells, inhibition of the interaction between T cells and antigen-presenting cells, blockade of T and B-cell recruitment, blockade of T-cell differentiation or activation, and blockade of pro-inflammatory cytokines.

Clinical data shows specific cytokines to be key players in the causation of the disease and thus inhibiting the cytokines using mAbs has shown to be an effective approach. Initial success was mostly achieved by the use of mAbs targeting TNF-α, an essential component in the inflammatory signaling cascade. While anti-TNF-α mAb alleviated rheumatoid arthritis (RA), it has also been found effective in treating other auto-immune diseases such as systemic lupus erythematosus (SLE), Crohn’s disease, ulcerative colitis, psoriasis, psoriatic arthritis, ankylosing spondylitis and juvenile RA. Some of the other approved mAbs include Tocilizumab/Actemra® or RoActemra® (anti-IL-6R) for both RA and juvenile idiopathic arthritis, Rituximab/Rituxan® (anti-CD20) for RA and Alemtuzumab/Lemtrada® (anti-CD52) for multiple sclerosis. Recently, fully humanized mAbs such as Belimumab/Benlysta® (anti-BLys) and Secukinumab/Cosentyx® (anti-IL17A) has been approved for SLE and psoriasis, respectively.

Monoclonal Antibody Therapy for Infectious Diseases

The limitations of hyperimmune sera from immunized animals and human donors, such as lot-to-lot variability, risk of pathogen transmission and immunological complications have paved way for mAb therapeutics in infectious diseases. These drugs specifically target viral or bacterial proteins, interfering with the lifecycle and/or eliciting an immune response. Antibodies can also be used to neutralize toxins in bacterial infections.

Palivizumab (Synagis®) is the first mAb approved for the prevention of the severe respiratory disease caused by respiratory syncytial virus in high risk populations. This mAb targets the F-protein, and inhibits virus replication and also reduces the frequency of the condition in infants. Ibalizumab (Trogarzo®) is another promising mAb, which was approved in 2018 for the treatment of multidrug-resistant HIV-1 infection. This blocks the viral entry into the host CD4+ T cells by binding onto the CD4 receptors and thus it plays a role as a post-attachment inhibitor. Also, anti-endotoxins directed against the lipid A of gram-negative bacteria have shown favorable outcomes in treating sepsis. Currently, several other promising mAbs are under development to prevent infectious diseases caused by Ebola virus, hepatitis B and C, herpes simplex virus, among others.

Monoclonal Antibody Therapy for other Therapeutic Areas

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Therapeutic Antibody Database

Download the list of therapeutic antibodies approved in the EMA (European Union’s FDA)