Antibody Drug Conjugates - SYNthesis med chem

Antibody-Drug Conjugates (ADCs) have been discussed for their therapeutic potential for over a century.

However, in the last 10 years, the field has gained momentum with the clinical approval of 13 drugs (see table below) with more expected to follow. All these drugs share one common feature, the targeting vehicle is a whole monoclonal antibody (mAb, IgG) with a molecular weight of 150 kDa, the variables are the conjugation chemistry used, the drug-loading and the combination of linker-drug (payload).

Trade Name	Approval Year	Drug	Payload
Mylotarg	2017	Gemtuzumab ozogamicin	Gemtuzumab ozogamicin
Adcetris	2011	Brentuximab vedotin	Brentuximab vedotin
Kadcyla	2013	Trastuzumab emtansine	Trastuzumab emtansine
Besponsa	2017	Inotuzumab ozogamicin	Inotuzumab ozogamicin
Lumoxiti	2018	Moxetumomab pasudotox	Moxetumomab pasudotox
Polivy	2019	Polatuzumab vedotin-piiq	Polatuzumab vedotin-piiq
Padcev	2019	Enfortumab vedotin	Enfortumab vedotin
Enhertu	2019	Trastuzumab deruxtecan	Trastuzumab deruxtecan
Trodelvy	2020	Sacituzumab govitecan	Sacituzumab govitecan
Blenrep	2020, withdrawn November 2022	Belantamab mafodotin-blmf	Belantamab mafodotin-blmf
Zynlonta	2021	Loncastuximab tesirine-lpyl	Loncastuximab tesirine-lpyl
Tivdak	2021	Tisotumab vedotin-tftv	Tisotumab vedotin-tftv
ELAHERE	2021	Mirvetuximab soravtansine	Mirvetuximab soravtansine

SYNthesis med chem Capabilities

For the past five years, SYNthesis med chem scientists have been involved in several projects related to Antibody Drug Conjugates, working alongside many different clients with different specifics to develop novel ADCs that incorporate innovative mechanisms of action. Our main focus has been on synthesizing different linkers and payloads /warheads.

Focusing on the synthesis of linker payloads/warheads

We have provided our clients with various payloads, linkers and conjugatable “building blocks”, allowing them to design and assess the potency, efficacy, and pharmacological properties of potential ADCs. Our scientists are highly skilled in the design and synthesis of a variety of payload and linkers, and are fully supported by our state of the art analytical facility.

PAYLOADS

We have successfully prepared a range of payloads, covering several mechanisms of action including microtubule polymerization inhibitors and DNA binders. Our bench chemists are fully trained to handle these cytotoxic warheads, which allow us to not restrict our offer to non cytotoxic warheads

Example of payloads we worked on:

Auristatins (e.g. MMAE, MMAF)
Pyrrolobenzodiazepines, Indolinobenzodiazepine and their derivatives
Duocarmycins and its derivatives
Camptothecin (e.g. SN38)
Some other innovative drugs designed by our collaborators

LINKERS

We have synthesised a range of cleavable linkers, based around peptides, glucuronides, disulfides and thioethers which are processed intracellularly to release the warhead or payload.

We have prepared a range of non-cleavable linkers based around peptide, carbohydrate, thioether and PEG components. These cleavable and non cleavable linkers have been readily attached to payloads or warheads, and have further incorporated reactive conjugatable groups that allow for lysine, cysteine and non-natural amino acid conjugation.