NRS 416 1.4 - Developing Biologics for Neuro Psych Disorders

Distinction

Small molecules and biologics are regulated under different rules, impacting:

• Their approval process

• How long they receive market protection from competitors - small molecules have 5-year exclusivity (plus extra for meeting certain criteria); biologics get 12 years

Small Molecule

• usually oral

• less expensive

• generics are usually interchangeable

• usually stable at room temperature

• can afect multiple systems, and predictable dose-dependent effects

Biologic

• usually injection

• more expensive

• biosimilars may not be interchangeable

• often require refrigeration, sterile conditions

• more targeted, but can cause injection site reactions and immune responses

Generics

exact chemical copies of brand-name small molecule drugs- must prove same concentration-time profile, implies same effects & adverse effects

Biosimilars

“highly similar" versions of complex biological products made from living sources – due to complexity of structures & manufacturing process may not be identical batch to batch, or between originator and biosimilar

Growth in Biological Therapeutics

Biologics now make up about a third of new drug approvals

• advances in fields of immunology and oncology

• Molecular biology & genetics tools and technologies allowing large-scale recombinant protein production & engineering

Types of Biologics

1. Peptides

   • vast majority of biologics on the market now are proteins (75-80%)

2. Nucleid acids

   • cell and gene therapies account for about 5-10%

3. Vaccines account for about 10-15%

Types of Therapeutic Proteins

1. endogenous proteins

2. Fc-fusion proteins

3. monoclonal antibodies (mAbs)

endogenous proteins

insulin and erythropoietin were among the first biologic therapies used clinically

Fc-fusion proteins

a combination of the Fc region of an IgG1 antibody with an endogenous enzyme or receptor (requires protein engineering)

monoclonal antibodies (mAbs)

part of the Ig family of glycoproteins, and are produced by B lymphocytes – classes include IgA through IgM, but therapeutic antibodies are almost all from the IgG class

STRUCTURE OF PROTOTYPICAL IgG ANTIBODY

1. Heavy chains

2. Light chains

3. Variable region / CDR

4. Constant region / Fc

Heavy Chains

main/supporting structure, determines class (e.g., IgG - immunoglobin G)

Light chains

shorter strands on arms, with recognizing/grabbing antigens

Variable region / CDR

the tips of the arms, billions of variations → extremely specific interactions with antigens

Constant region / Fc

tells immune system how to destroy the antigen (effector functions)

EARLY ANTIBODY DRUGS

• An antigen (whole or part) is injected into an animal several times over months to allow the animal to generate an immune response

• Perpetually replicating tumor cells are fused with B cells that make antibodies to that antigen

• Cell fusion produces a hybridoma, which continually makes antibodies

Monoclonal antibodies

produced by one cell (all mAbs recognize the same epitope)

polyclonal antibodies

many B cells make antibodies against many epitopes

chimeric mAb drugs

made to avoid problem of instantly triggering formation of antibodies or generalized immune responses

• had fewer/less severe adverse effects, but still encountered problems with forming anti-mouse antibodies

• meaning parts from various animals

-momab

mouse

-ximab

chimeric

-zumab

humanized

-umab

fully human

Target Location

• small molecules: can be intra- or extracellular

• biologics: usually must be in plasma or on cell surface (extracellular), due to size and physiochemical properties

Target Identification

same process in small molecules and biologics → relies on basic knowledge of the role of the target under normal and disease conditions

Hit Generation

• small molecules - screening structure libraries, using synthetic chemistry to make molecules that interact with target

• biologics - creating mAbs against a target antigen (e.g., hybridomas, phase display technology)

Target Affinity

generally much higher for biologics, due to specificity and extreme tightness of antibody-epitope interactions

Lead Optimization

• small molecules - iterative cycles of synthetic chemistry and determining impact on key properties of interest

• biologics - usually protein engineering of Fc region to improve drug-like properties, minimize unwanted effector functions, or optimize more complex functions:

  • Antibody-drug conjugates (ADCs) may have to release their payload in the right place at the right time

  • Bispecific antibodies (BsAb) bind two different epitopes → more accurate targeting

PRECLINICAL PHARMACOLOGY

Both small molecule and biologic drugs use human cellular or animal model systems to establish the mechanism of action

Biologics can pose additional challenges related to species differences and the tendency to interact with the immune system, requiring approaches such as:

• Making a mouse version of a human antibody to enable testing in mice

• Transgenic animals that express the human target of the mAb (human mAb can be immunogenic, requiring immunocompromised mice)

Administration route

usually limited to subcutaneous or IV injections for biologics

• biologics are mainly proteins so if ingested orally, they would be destroyed

Absorption & Distribution

both slower for biologics, due to difficulty crossing membranes; since biologics don’t cross membranes well, they also tend not to distribute into cell nuclei, minimizes risk of genotoxicity

Metabolism

biologics are broken down into component amino acids (which are

recycled as nutrients), minimizes risk of toxic metabolite formation

Half-Life

time it takes for drug concentrations to fall by half – is generally much longer for biologics due to their large size

FIRST-IN-HUMAN STUDIES

Selecting a safe starting dose can be difficult with biologics

• 2006 Phase I trial of TGN1412 (an anti-CD28 mAb for treating B-cell lymphoma) based starting dose on data from monkeys

• That dose caused massive cytokine storm in all 6 subjects, who required ICU organ support for weeks (all survived though)

• Led to overhaul of regulations for biologics, requiring 30,000-fold lower starting doses, and monitoring of a single sentinel subject first

SUCCESS VS FAILURE RATES

One reason biologics have been making up an increasing share of new approvals is that they tend to have a higher development success rate

• Target specificity – biologics bind tightly and selectively to their target, minimizing off-target effects (leading cause of small molecule failure)

• Lower toxicity – biologics have minimal genotoxic and toxic metabolite issues

• Biologics have more predictable metabolism / fewer drug-drug interactions