Catapano AL, Papadopoulos N.
Atherosclerosis. 2013 Feb 8. doi: 10.1016/j.atherosclerosis.2013.01.044.

Although good results in lowering the incidence of CV events can be obtained by lowering LDL-C, part of the patient population fails to reduce their LDL-C to recommended levels, or does not tolerate the commonly used statins. Thus, new treatment strategies are required. One of the approaches currently being developed is the use of monoclonal antibodies (mAbs).
mAbs have become established therapies for a number of disorders, including cancer and immunological diseases. Much effort has already been dedicated to studying mechanisms of distribution, potency, specificity, immunogenicity and dosing frequency.
To date, the only mAb licensed for the treatment of CV-related disorder is abciximab, which is used after PCI and for unstable angina. A newly developed class of mAbs targets PCSK9 (see below), which has the potential to manage CV risk in patients in whom existing therapies fail to lower LDL-C.

We here summarise the main points outlined in this review.

How do mAbs work?

mAbs can directly interact with a target and change its biological function or they can interact with cell surface receptors, which then induce immune-mediated downstream effects, such as cytotoxicity. Alternatively, when a mAb is bound to its targets, the complement system can be activated, with subsequent induction of cytotoxicity.

How are they made?

First generation therapeutic mAbs were made in mice. Patients treated with murine immunoglobulins often developed human antimouse antibodies  (HAMAs), resulting in rapid mAb clearance. A solution for this problem was the fusion of a mouse antigen-binding domain to a human constant domain. These chimeric and humanised mAb caused less HAMA formation, but also decreased binding affinity. More recently, fully human mAbs have been produced, which show less immunogenicity than murine and chimeric mAbs. Already nine fully human mAbs have been approved for therapeutic use in Europe and the United States.

Primary safety concerns

The direct interaction with the target molecule and/or processes may result in adverse effects (AE). AEs could be due to the intended pharmacological action of the mAb, or mAbs may cause toxicity by interacting with the target antigen outside the target tissue. Furthermore, off-target, non-specific toxicity can be observed, such as hypersensitivity reactions thought to be related to immunogenicity of mAbs. This risk has greatly been reduced, but not entirely eliminated, by the development of fully-human mAbs.
Overall, the risk of serious adverse drug reactions with mAbs is generally low. mAbs are generally well-tolerated and safety profiles seem relatively stable over time.

mAbs for the treatment of CVD

The first mAbs have been developed for treatment of CVD or its risk factors:

• Abciximab: inhibits platelet cross-linking and aggregation by targeting glycoprotein IIb/IIIa, thus reducing blood coagulability, to be used in patients undergoing PCI. It is a chimeric mAb, which likely explains its off-target, non-specific AEs. Specific AEs are also seen, such as increased risk of bleeding and thrombocytopaenia.
• PCSK9 mAbs: target proprotein convertase subtilisin/kexin type 9 (PCSK9). This serine protease is responsible for post-transcriptional regulation of LDL-receptor (LDLR) levels. PCSK9 normally binds to the LDLR and stimulates its internalisation and degradation. Reduced availability of LDLR leads to higher plasma LDL-C.
• Thus, blocking the interaction between PCSK9 and LDLR by mAbs targeted against PCSK9 will likely reduce CV risk in people with hypercholesterolaemie. It is anticipated that PCSK9 mAbs may also increase the lipid-lowering efficacy of statins.

Efficacy and safety of PCSK9 mAbs

Genetic variation in the PCSK9 gene can influence affinity to LDLR and thereby plasma cholesterol levels, with concomitantly altered coronary heart disease risk. Both gain-of-function and loss-of-function PCSK9 mutations have been described, leading to increased and reduced CV risk respectively.
Pre-clinical studies with several PCSK9 mAbs developed by several pharmaceutical companies showed a promising reduction of serum cholesterol in several species (rodents, primates).
Phase I trials in healthy subjects and hypercholesterolaemie showed that PCSK9 mAbs are generally well-tolerated and significantly reduce LDL-C (study details are discussed in the review).
The first phase II clinical studies have recently been completed, studying different dosing regimens as well as combination therapies with statins. Details are discussed in the review.

Conclusion

Despite its novelty for the treatment of hypercholesterolaemie, current data indicate that a fully human PCSK9 mAb gives clinically meaningful reductions in LDL-C in patients, irrespective of statin treatment. No potential on-target adverse effects of blocking PCSK9 have been identified to date. However, these conclusions are based on small-scale studies and limited exposure. Ongoing, larger studies of longer duration will have to assess the long-term efficacy and safety, and its use in a wider range of patients.

Abstract

Monoclonal antibodies (mAbs) are established therapies for many conditions, including cancers, autoimmune conditions and infectious diseases. mAbs can offer benefits over conventional pharmacotherapy in terms of potency, dosing frequency and specificity for their target antigen. Mouse-derived antibodies were initially used in humans; however, patients often developed human anti-mouse antibodies, resulting in rapid antibody clearance (and a resulting loss of efficacy) and hypersensitivity reactions. Chimeric, humanized, and fully human antibodies were thus developed, with increasing amounts of human sequence, to reduce immunogenicity. Although generally well tolerated, mAbs may be associated with adverse events (AEs). Many AEs are target-related, and will be specific to the antibody target and the therapeutic area of use. However, off-target AEs, such as hypersensitivity reactions, are observed with many antibodies. Within the realm of cardiovascular medicine, new antibody-based therapies are under investigation to reduce low-density lipoprotein cholesterol (LDL-C) levels. Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates plasma LDL-C levels by increasing degradation of the LDL receptor (LDLR). Therefore, inhibition of the interaction between PCSK9 and the LDLR with mAbs targeting PCSK9 has great potential for patients with hypercholesterolaemia. Early clinical phase studies suggest these mAbs are effective and well tolerated; however, further studies are required to assess their long-term safety.