Antibody Drug

Conjugates for
Cancer Presented By: Anvita Jadhav
M. Pharm (IP)

What are ADCs ?????????????????

Antibody-drug conjugatesor ADCs are a new class
of drugs designed as atargeted therapyfor the
treatment of cancer.

ADCs

are

complex

molecules

composed

of

anantibodylinked, via a stable linker with labile

bonds, to acytotoxic(anticancer) drug.

ADC timeline
1958

Schematic
illustration of ADC

Mechanism of Action
1

Mechanism of Action

Antibody

Antigen Binding Sites

immunoglobulins made

Fc Region

up of:
2 Light Chains (identical)
~25 KDa
2 Heavy Chains
(identical) ~50 KDa

Fab Region

Antibodies are

Terminology

MAb: Monoclonal Antibodies

From a biology perspective, the design of an effective

ADC relies on
Selection of an appropriate target antigen

Target antigens
A successful ADC should target a well-internalized
antigen with low normal tissue expression and high
expression on tumors.

Antigen expression on normal tissues can be tolerated if

expression on vital organs is minimal or absent.
Target antigens for ADCs in preclinical & clinical
development
Cancer

Target Antigens

Breast

CD174, GPNMB, CRIPTO & nectin-4 (ASG-22ME)

Ovarian

MUC16 (CA125), TIM-1 (CDX-014) & mesothelin

Lung

CD56, CD326, CRIPTO, FAP, mesothelin & GD2

Pancreatic

CD74, CD227 (MUC-1) & nectin-4 (ASG-22ME)

Prostate

PSMA, STEAP-1 & TENB2

Antigen expression
In general, optimal ADC targets are homogeneously
and selectively expressed at high density on the
surface of tumor cells.
Homogenous tumor expression (although preferred)
is likely not an absolute requirement.

Antigen internalization
Ideally, once an ADC binds to a tumor-associated target,
the ADCantigen complex is internalized in a rapid and
efficient manner.
Factors influencing the rate of internalization, such as Epitope on the chosen target antigen bound by the ADC
Affinity of the ADCantigen interaction
Intracellular trafficking pattern of the ADC complex

Impact of format
The biological activity of an antibody can depend on
the interaction of its Fc portion with cells that express
Fc receptors (FcRs).
Therefore, selection of the appropriate antibody
format for an ADC is an important consideration.

Classification of linkers
Linkers
Cleavable
Noncleavable
Lysosomal
Acid
Glutathione
sensitive
linkers
protease
sensitive
linkerssensitive
linkers linkers

Cleavable linkers

Lysosomal protease sensitive

linkers

This strategy utilizes lysosomal proteases, that recognize and cleave

a dipeptide bond to release the free drug from the conjugate.

Eg.: Valine - Citrulline linker

Acid sensitive linkers

This class of linkers takes advantage of the low pH in the lysosomal

compartment to trigger hydrolysis of an acid labile group within the
linker, & release the drug payload.

Eg.: Hydrazone linker

Glutathione sensitive linkers

This strategy exploits the higher concentration of thiols,

such as glutathione, to release the free drug.

Eg. Disulphide linker

Noncleavable linkers

This approach depends on complete degradation of the

antibody after internalization of the ADC, resulting in
release of the free drug with the linker attached to an
amino acid residue from the mAb.

Noncleavable linkers has greater stability in circulation

compared with cleavable linkers.

Cytotoxic drugs

The drugs being used to construct ADCs generally fall into

two categories:
1) Microtubule inhibitors
2) DNA-damaging agents

The percent of an injected antibody that localizes to a solid

tumor is very small (0.0030.08% injected dose per gram of
tumor); therefore, toxic compounds with sub-nanomolar
potency are desirable.

ADC Design
Targets a wellAntibody
characterized
antigen

Maintains
binding,
stability,
internalization,
etc.

Drug Conjugates

Highly potent
Non-immunogenic
Amenable to
modifications for
linker attachment

Cleavable or noncleavable

Minimal
nonspecific
binding

Stable in circulation
Selective intracellular
release of drug

Chemical conjugation

Traditionally, conjugation of linker-drugs to an antibody

takes place at solvent accessible reactive amino acids such
as lysines or cysteines derived from the reduction of
interchain disulfide bonds in the antibody.

Lysine conjugation

Results in 08 conjugated molecules per antibody

Conjugation occurs on both the heavy and light chain at

~20 different lysine residues (40 lysines per mAb).

Greater than one million different ADC species can be

generated.

Cysteine conjugation

Cysteine conjugation occurs after reduction of four interchain disulfide bonds.

Linker-drugs per antibody can range from 08, generating

more than one hundred different ADC species.

Drawbacks of Chemical conjugation

Therefore, eachconsistency
species mayinhave
in in-vivo
PK properties.
Batch-to-batch
ADC differ
production
is difficult
to obtain
ADC species differ in drug load & conjugation site.

Site-specific conjugation
It has three strategies

ADC advantages over

Traditional Chemotherapy
Traditional Chemotherapy

Merits of ADC

Selective delivery to tumor cells

Specific binding to target antigen

Large therapeutic index

Reduction of adverse effects

Extended and prolonged circulation half life

Demerits of ADC

Molecular targets having similar expression may also get

exposed to the drug

Requires screening of antigen of interest

Premature release of cytotoxic drug

Sufficient concentration may not be achieved at target site

Characterization of ADC
Drug to Antibody Ratio (DAR)

Approved ADCs
Agent
Adcetris
(brentuximab
vedotin)

Indication
HL, ALCL

Antigen
CD30

Cytotoxin
MMAE

Linker
Cleavable

Kadcyla
(trastuzumab
emtansine)

Her2+ metastatic
breast cancer

HER2

DM1

Non-cleavable

ADCs under Clinical Trials

Agent

Status Indication

Antigen

Cytotoxin Linker

Glembatumumab
vedotin

Ph II

Advanced
breast
cancer

GPNMB

MMAE

Cleavable, Val-Cit

Lorvotuzumab
mertansine

Ph II

MM, solid
tumors

CD56

DM1

Cleavable, disulfide

BT-062

Ph I

MM

CD138

DM4

Cleavable, disulfide

ADCs are a new class of drugs designed as atargeted therapyfor t

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