Biologics.pdf

Biologics Biologics - They are generally: o Formulated as injectables (IV, SC) o Transported using cold-chain and refrigerated for long-term storage. o Administered by a health care practitioner. (exception insulin) Definitions From amino acids to proteins – pri...

Biologics Biologics - They are generally: o Formulated as injectables (IV, SC) o Transported using cold-chain and refrigerated for long-term storage. o Administered by a health care practitioner. (exception insulin) Definitions From amino acids to proteins – primary, secondary, tertiary, and quaternary protein structures. What are biologics? - Active substances made by or derived from a biological source, rather than a chemical source or synthesised chemically. - These are either relatively small molecules such as human insulin or erythropoietin or large and complex molecules such as monoclonal antibodies or cells such as T-cells. - Typically, are proteins or proteins containing agents produced using biotechnology (e.g. recombinant DNA techniques) and manufactured in cell culture or living organisms including humans, animals, or microorganisms. Wide range of biologic medicines - Antibodies and antibody-based therapeutics and recombinant therapeutic proteins. o Monoclonal antibodies o Alternative mAb-based therapeutics § Fc-fusion proteins § Antibody-drug conjugates § Bispecific antibodies § Immune checkpoint inhibitors - Therapeutic signalling molecules o Peptide and protein hormones § Insulins and glucagon like peptide analogues. § Growth hormone, gonadotropins and other hormones. o Hematopoietins and related molecules. § Colony-stimulating factors. § Erythropoietin. - Blood related products. o Recombinant coagulation factors. o Anticoagulants and thrombolytic agents. - Biosimilars - Somatic cells, gene-based and cellular therapies, and tissues. - Vaccines What is a biosimilar? - A biological product that is ‘highly’ similar to and has no clinically meaningful diPerences from an approved reference product. - ‘Highly’ – extensively characterise structure and function of the reference and the proposed biosimilar product. Chemical identity, purity and bioactivity compared to demonstrate that the biosimilar is ‘highly’ similar to the reference product. - Minor diIerences between the reference product and the proposed biosimilar product in clinically inactive components are acceptable. - A biosimilar has no clinically meaningful diIerence in terms of purity, safety, and potency (safety and ePectiveness). - Abbreviated approval pathway, e.g., no dose ranging studies. What is a biobetter (biosuperior)? - Biobetters are related (but not identical) to existing biologics by target of action but deliberatively improved in manufacturing attributes, disposition, ePicacy and safety. - Biobetters build on the success of an existing approved biologic but present a lower commercial risk than a new class of biologic. Interchangeability, switching & substitution. - Interchangeability: o the medical practice of changing one medicine for another to achieve the same clinical ePect in a given clinical setting and, in any patient, on the initiative of, or with the prescriber’s agreement. An interchangeable product is a biosimilar that produces the same clinical outcome in any given patient. - Switching: o Decision by treating physician to exchange one medicine for another with the same therapeutic intent in a given patient. - Substitution: o Dispensing one medicine instead of another equivalent/interchangeable medicine by the pharmacist without consulting the prescriber. Pivotal diIerences – comparison of biologics and small molecule drugs Why is it diIicult to develop biologics? Size of biologics Structural features of various classes of therapeutic proteins - Large molecules à recycled by body à half-life is long, not filtered through kidney à require fewer injection. - Insulin à cleared easier from body, requires frequent injection. Glycosylation - Types of N-glycans observed in therapeutic proteins. All N-glycans are composed of the core structure. Why is it diIicult to develop biologics? - Manufacturing & post-translational modifications (PTMs) - Aggregation / misfolding – most common for recombinant proteins. - Oxidation (of methionine) and sometimes of other amino acids. - Deamidation (of asparagine) and sometimes of other amino acids. - Glycosylation heterogeneity – specific to the protein and dependent on expression system. - Human pathogen transmission (similarity or otherwise of expression host to human cells) - Hydroxylation (primarily proline); Sialyation and carboxylation. - Sulphation – specific to surface exposed tyrosine residues surrounded by acidic residues. - Profoundly aPect proteins and their therapeutic application requiring biophysical and functional assays to ensure stability, ePicacy and safety. Therapeutic monoclonal antibodies (mAbs) The antibody revolution What are mAbs and their action? - Monoclonal antibodies (mAbs) are targeted therapy agents – large proteins (>1000 aa) produced through genetic engineering. o They usually have to be given IV or SC. o Bind antigen. Bind Ag through loops at its tips, and may block its action, or crosslink receptors (and lead to loss from cell surface or apoptosis) o Stays in serum for 14-28 days (half-life) o Side ePects can include reactions to non-human proteins. o Kill. They can cause cell damage in several ways, most often by attacking cell-surface receptors. § Fc domain acts as flag leading to killing of agent by engaging C1q, TRIM21, neutrophils, macrophages & NK cells. Depends on whether IgG1,2,3 or 4. Therapeutic mAb Development Antibody dependent cell mediated cytotoxicity. - EPector cells – NK cells, mononuclear phagocytes, neutrophils. - ADCC can be amplified by high tumour antigen density, high aPinity Fc receptors, NK cell activation strategies. - High antibody aPinity promotes in vitro ADCC. Engineered mAbs. Types of mAbs Biosimilars - Many issues need to be satisfied: - Manufacturing issues: o Complexity o It must be similar to that of originator drug. o It will be impossible to make them same - IP issues - Biosimilar should have ‘no meaningful clinical diPerences’ between originator & biosimilar. - Safety issues. - Other points to consider: o Vague guidelines. o When / how can we ‘switch’ them to biosimilars? o Need to educate healthcare providers & consumers. o Insurance issues? Pharmaceutical mAbs - Humira (adalimumab) - Rituxan (Rituximab) - Cetuximab - Trastuzumab - Bevacizumab Antibody Drug Conjugates (ADCs) - mAbs joined to a chemotherapy drug or to radioactive particle are called conjugated mAbs. - Examples of approved mAbs: o Radio-conjugated antibodies § Tositumomab (Bexxar) § Ibritumomab (Zevalin) § Both used against refractory lymphomas. o Toxin-conjugated antibody § Gemtuzumab ozogamicin (Mylotarg) § Used against AML ADC structure Bispecific Bispecific mAbs - Binds to two targets simultaneously, e.g. cancer cell and an immune cell. - IgG like or non-IgG like. - Currently approved bispecific: o Blinatumomab: targets CD19 and CD3, used for acute lymphoblastic leukemia (ALL) o Emicizumab: targets clotting factors IXa and X, used for haemophilia A. Antibody-targeted gold nanoparticles - Non in the market yet. Immune checkpoint inhibitor - A type of drug that blocks proteins called checkpoints that are made by some types of immune system cells, such as T cells, and some cancer cells. These checkpoints help keep immune responses from being too strong and sometimes can keep T cells from killing cancer cells. - 하지만 염증반응이 과하게 일어나는 것은 오히려 몸에 해롭기 때문에, 우리 몸은 면역관문을 통해 과도한 면역반응을 적절히 조절합니다. 이 관문이 제대로 작동하지 못할 경우에는 면역 항진에 의한 자가면역 질환이 발생하며, 면역 상태가 항진이라는 것은 인체의 높은 염증반응 때문에 염증 질환이 쉽게 발생할 수 있음을 뜻합니다. 아울러 암세포의 작용을 억제하는 것 또한 면역관문억제제입니다. 암세포는 우리 몸에서 살아남기 위해 면역관문을 조종해 마치 정상 세포인 것처럼 꾸며 면역세포로부터 자신을 보호하는데, 이때 암세포가 면역세포를 피해 가는 기전을 억제함으로써 면역 세포가 암을 공격해 없앨 수 있게 됩니다. DiIerences in properties of pharmaceutical drugs Concluding remarks & take-home messages - There are many diPerent types of biologics. - Science is complex and data is changing exponentially as newer analytical tools become available. - Greater economic pressures from governments/third-party payers for cheaper versions of biologics; biosimilars. - Science is changing at a faster rate than the ability of regulators/policy makers to keep pace and embed regulatory frameworks. - Imperative that Pharmacists keep abreast of such rapid changes as they will be expected to facilitate conversations with physicians and patients. - Molecularly targeted therapy is a new way of approaching cancer treatment (and other disorders) - It is based on recent scientific advances in molecular biology, chemistry, and genetics. - It involves the rational selection of drugs which target specific processes in diseased cells (e.g., cancer) that make them diPerent from normal cells. - A number of targeted therapies are currently available, and many others are in development. - Targeted therapies are frequently ePective but are not perfect: There are side ePects to the treatments, and there may be development of resistance. - Targeted therapies are increasingly being used in combination with other targeted therapies or with other treatment modalities. - We will be hearing much more about targeted therapies for many indications including autoimmune disorders and cancer in the future.