The path of the "magic bullet"

Around the turn of the last century, Paul Ehrlich postulated that tailored and targeted drug delivery might be a means of treating disease1. Some eighty years later, the "magic bullet" concept was realized with successful delivery of a cytotoxic drug to tumors in situ using a cancer-recognizing antibody2

During the 1990s, the availability of tumor antigen-specific monoclonal antibodies spurred attempts to develop antibody-drug conjugates (ADCs), with results largely serving to underscore the truism that, while ADCs are deceptively simple in concept, success demands precision alignment of antibody, linker, and toxic payload properties.

Tumor biology shapes ADC design. To minimize off-target toxicity and maximize killing effect, the target antigen must have higher expression in tumors versus normal tissues. Here be dragons- “tumor-associated” is not the same as “tumor-specific”3. The target must be accessible on the plasma membrane of cancer cells, but not released in quantity into the bloodstream, and to become internalized on ADC binding to trigger drug release. Other considerations in target selection include heterogeneity of expression within the tumor, although toxin release from target expressing cancer cells can kill their non-expressing neighbors - the so-called “bystander effect”, and high expression by both primary and metastatic tumors.

Essential characteristics of the corresponding antibody are high specificity and affinity for the target antigen, a long plasma half-life, a fast rate of internalization, and low immunogenicity. Linker chemistry dictates ADC stability and efficacy, with choice balancing the requirements for minimal release of payload while in circulation, low propensity to cause aggregation of the ADC complex, and the rate of payload release.

With non-cleavable linkers, on ADC binding and internalization, the antibody component is broken down by lysosomal enzymes, generating a peptide-payload conjugate that does not easily pass through membranes and have little bystander effect. Cleavable linkers result in faster delivery of an unmodified payload and a higher likelihood of bystander effect, although also off-target effects.

The key requirements of high potency, solubility, in vivo stability, membrane permeability and amenability to conjugation make for a short list of ADC payload choices. Useful agents include certain classes microtubule inhibitors (auristatins, maytansinoids); DNA-damaging agents (calicheamicin, camptothecin analogues, duocarmycin and pyrrolobenzodiasepine dimers), and the topoisomerase inhibitor, SN-38.

The early years

The first ADC to receive marketing approval (May 2000) was Mylotarg® (gemtuzumab ozogamicin: Pfizer), initially for the treatment of relapsed or refractory acute myeloid leukaemia (AML) expressing CD33. Real life clinical experience and a confirmatory Phase III study uncovered efficacy and safety issues, resulting in its voluntary withdrawal in 2010. Evaluation of lower dosing and chemotherapy combinations allowed a return to the market in 2017, with the FDA granting approval for use as first-line or subsequent therapy in adult and paediatric AML.

ADC development experienced some patchy success after 20104. Adcetris® (brentuximab vedotin: Seattle Genetics, now Seagen Inc) received marketing approval in August 2011, initially for relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma, since expanded to include other forms of lymphoma and to its use in children. A key feature of Adcetris® design was incorporation of a highly stable cleavable linker. Improved, toxicity-reducing, non-cleavable linker chemistry was also a key feature of Kadcyla® (ado-trastuzumab emtansine: Roche), the first ADC to achieve approval for a solid tumour indication (HER2-positive metastatic breast cancer) in February 2013, since expanded to the treatment of earlier-stage breast cancer.

Solid tumor successes

Despite a steep learning curve with respect to component selection and manufacture, ADC development has managed to escape its troubled past. Further improvements in linker chemistry and a broader choice of cytotoxic payloads have resulted in an increase in ADC approvals since 2017, a full clinical development pipeline and regular high value deal-making. What might once have been viewed as a niche oncology drug class now features large in global pharma portfolios.

ADC therapy has gained greatly from its high-profile clinical successes in hard-to-treat tumors. Like Kadcyla®, Enhertu® (trastuzumab deruxtecan: Daiichi Sankyo & Astra Zeneca) is a HER-2 specific ADC, initially gaining accelerated approval (December 2019) on the strength of progression free survival (PFS) and objective response rates (ORR) in heavily pre-treated metastatic breast cancer patients. The confirmatory DESTINY-Breast03 study demonstrated improvements in PFS and ORR over Kadcyla® and a trend towards improvement in overall survival.

Around 15-20% of breast cancers are HER-2 positive by immunohistochemical testing. The DESTINY-Breast 04 study evaluated Enhertu® in woman with previously treated "low HER-2"advanced breast cancers. Enhertu® achieved a 36% reduction in the risk of death when compared with physician’s choice of chemotherapy. FDA approval was extended to low HER-2 breast cancer in August 2022. Enhertu® is also approved for the treatment of HER-2 expressing gastric and non-small cell lung cancers (NSCLC).

Trodelvy® (sacituzumab govitecan: Immunomedics, now Gilead) targets Trop-2, a protein overexpressed in several types of solid tumour. FDA approval was granted in April 2020 on the strength of data from the ASCENT study, where Trodelvy® was found to reduce the risk of death by 52%. FDA approval was granted for the treatment of advanced triple negative breast cancer in April 2020, for advanced bladder cancer in April 2021, and most recently, HER-2 negative breast cancer (February 2023). Trodelvy® is under evaluation in NSCLC and other solid tumors.

ADC-driven business development

Daiichi Sankyo expects Enhertu® global revenue to exceed $1.5 billion in 2023, while another $2.5 billion has been received in upfront, milestone and royalty payments through its licensing agreement with Astra Zeneca. Trodelvy® earning potential was considered a major factor in the acquisition of Immunomedics for $21 billion by Gilead in September 2020, although 2022 global sales of Trodelvy® were a modest $680 million.

After waltzing with Merck & Co, Seagen has now fallen into the arms of its fellow ADC pioneer, Pfizer, with the companies agreeing an acquisition price of $43 billion. Post-merger, Pfizer's oncology portfolio will feature six out of 14 FDA approved ADCs, together with an expanded pipeline of clinical-stage ADC candidates and Seagen's decades-deep ADC expertise. Merck has not been completely frozen out: an existing Seagen collaboration on development of an ADC targeting the zinc transporter transmembrane protein LIV-1 as a solid tumor treatment will survive the merger.

Significant challenges remain when it comes to safely maximising ADC potency. Continuing need for optimised antibodies, better linkers and conjugation-friendly, highly potent payloads has created a healthy development ecosystem, encompassing academic innovation, early-stage and small-cap technology specialists and experienced contract development and manufacturing organizations (CDMOs).

This makes for busy technology licensing. During the past year, Amgen licensed Synafix's linker and payload technology for a headline value of $2 billion, adding to an already long list of licensing agreements with global and mid-sized pharma companies; Merck KGaA entered a research collaboration and licensing agreement with Mersana Therapeutics (terms undisclosed) to gain access to the latter's  STING-agonist ADC platform; Lonza, a major provider of ADC development services recently formed a strategic collaboration with Simris Biologics, giving access to the company payload platform. BioNTech recently partnered with Duality Biologics to access two investigational ADCs bearing topoisomerase I inhibitor payloads, with a headline deal value of over $1.6 billion excluding royalties for ex-China rights.

Exelixis, a successful small molecule drug developer, is building an ADC pipeline through multiple technology licensing agreements: including Catalent's SMARTag site-specific modification and linker platform; NBE-Therapeutics’ (now Boehringer Ingelheim) proprietary antibody display, linker, and payload technologies, and BioInvent's target and antibody discovery platforms. The development candidate XB002, a tissue factor-specific ADC incorporates an antibody acquired from Iconic Therapeutics and linker and payload technology from Zymeworks. Another candidate ADC, XB010 was developed in collaboration with Invenra and Catalent.

What’s next?

ADC development has successfully beaten substantial technical challenges in the past two decades, but it’s recognized that further improvement is required to realize the broader potential of ADC and for it to remain competitive in the ever-changing landscape of precision cancer therapy.

New targets could expand the number of cancers addressable by ADCs. PYX-201 (Pyxis Oncology, originally developed by Pfizer) is unusual in that it targets a non-internalizing antigen, fibronectin extra-domain-B (EDB fibronectin) which expressed in the extracellular tumour matrix. Cleavage results in diffusion of the toxic payload across cancer cells and tumour-supporting fibroblasts and vasculature, with the bonus of a bystander effect.

ADCs specific for Claudin 18.2, a tight junction protein which becomes exposed when gastric epithelial cells become malignant, have been developed by Elevation Oncology (EO-3021), RemeGen (RC118), Keymed Biosciences (CMG901), and SOTIO Biotech (SOT102).

ADC Therapeutics is evaluating ADCT-601, an ADC targeting the tyrosinase kinase AXL, a driver of tumour spread and recurrence, in sarcoma patients. Genmab discontinued its own AXL-specific ADC (AXL-107) due to poor efficacy in early clinical studies. A high incidence of anaemia in clinical trials of CX-2029, a transferrin receptor-specific ADC, an usual choice of target, being expressed by both tumors and normal tissues, was given as the reason for abandonment of co-development by AbbVie, with return of rights to Cytomx under negotiation.

ADC development could benefit greatly from an expanded choice of payloads. The PNU anthracycline, PNU-159682, is more potent than tubulin-targeting payloads by several orders of magnitude. The technology, together with early clinical-stage candidates, was acquired by Boehringer Ingelheim on acquisition of NBE Therapeutics in October 2020. PNU-159682 is the payload delivered by SOT102, currently in early clinical study in gastric cancers.

Heidelberg Pharma (previously Wilex AG) hopes to capitalize on the RNA polymerase II inhibitor, amanitin, one of several related toxins responsible for giving the death cap mushroom (Amanita phalloides) its deadly reputation. A Phase I/II study of HDP-101, a B-cell maturation antigen-specific ADC bearing an amanitin payload is ongoing in multiple myeloma patients.

AbbVie is evaluating a novel BCL-XL (B-cell lymphoma extra-long) inhibitor payload delivered by the B7H3-specific ADC, ABBV-155 as a monotherapy and in combination with taxane chemotherapy in subjects with advanced refractory solid tumours, including NSCLC, small cell lung cancer and breast cancer in an ongoing Phase I/II study. Interim analysis indicated a tolerable safety profile on dose-escalation.

Derivatives of cyanobacterial toxins are already exploited in licensed ADCs. Simris Biologics (formerly Cyano Biotech) believes that its proprietary microcystins, derived from non-ribosomal peptide toxins can tick the boxes when it comes to superior ADC payloads. Preclinical data indicates high potency with no significant off-target effect and compatibility with cleavable and non-cleavable linkers and different conjugation chemistries.

Several companies are pursuing ADCs armed with non-cytotoxic, immunomodulating payloads. While clinical development of ImmunoTAC™ SBT6050 (Silverback Therapeutics), a HER-2 antibody-TLR8 agonist ADC, was terminated in early 2022 due to limited efficacy and safety issues, Bolt Therapeutics recently reported promising Phase I safety and efficacy data for BDC-1001, a HER-2 -antibody- TLR7/8 agonist, under evaluation as both monotherapy and in combination with an anti-PD-1 immune checkpoint inhibitor in patients with HER-2 expressing solid tumours. The first-in-human study of Mersana’s XMT-2056 ADC candidate, comprising a HER-2 antibody and a STING agonist payload is currently on clinical hold following a fatal adverse event.

ASP-1929 (Rakuten Medical) combines the licenced EGFR-specific antibody cetuximab with a laser-activated dye, IR700. After accumulation of the ADC at the tumour, the site is illuminated with a non-thermal red-light laser, causing local generation of reactive oxygen species and damage to the tumor cell. The ADC is inert in its unbound state. ASP-1929 received marketing approval in Japan (September 2020) for the treatment of unresectable head and neck cancers and is in clinical evaluation against recurrent and earlier-stage head and neck cancers.

ADC has still to find application outside of cancer treatment. There are some early hints of potential in autoimmune disease. AbbVie researchers have shown that ABBV-3373, an ADC specific for immune cell-bound tumour necrosis factor (TNF), comprising the long-established therapeutic antibody, adalimumab (Humira®) coupled to a proprietary glucocorticoid receptor modulator can modulate inflammation in an animal model of arthritis5.

ABBV-3373 is under evaluation in a head-to-head comparison with adalimumab treatment in rheumatoid arthritis patients. While modest in size (48 subjects), interim analysis suggests a high probability that ABBV-3373 will prove superior to adalimumab treatment on, and without additional safety concern 6. Another TNF-specific, glucocorticoid receptor modulator-bearing ADC, ABBV-154 is under evaluation in subjects with Crohn’s disease and polymyalgia rheumatica, a painful inflammatory condition. Takeda, in partnership with Innate Pharma, is aiming to explore the potential of ADCs in the treatment of celiac disease.

Autologous hematopoietic stem cells transplantation (auto-HSCT) is a treatment of last resort for some individuals suffering from multiple sclerosis and other autoimmune conditions, bringing about a "reset" of the patient's immune system to restore immune tolerance. Magenta Therapeutics has demonstrated that treatment with an ADC specific for CD45, a protein expressed on most types of immune and stem cells, can bring about immune reset in animal models of multiple sclerosis, systemic sclerosis, and inflammatory arthritis7. However, advancement of this concept into the clinical must be in doubt following a recent halt on clinical evaluation of the company’s lead ADC pre-transplant conditioning agent.


Whether non-cytotoxic payloads and diffusion into the treatment of high-burden chronic autoimmune conditions will drive the next stage of ADC evolution remains to be seen, but current momentum in ADC development and high probability of incremental improvements in design and manufacture will continue to produce new and more patient-friendly cancer treatments against an expanding list of indications. Ehrlich’s “magic bullet” concept looks likely to still be exploited in the next century.


1 Ehrlich P. Zur Kenntnis der Antitoxinwirkung. Fortschr Med. 1897; 15:41–43

2 Ford CH et al. Localisation and toxicity study of a vindesine-anti-CEA conjugate in patients with advanced cancer. Br J Cancer. 1983 Jan;47(1):35-42

3 Tolcher AW. Antibody drug conjugates: lessons from 20 years of clinical experience. Ann Oncol. 2016 Dec;27(12):2168-2172

4 Joubert N et al. Antibody-Drug Conjugates: The Last Decade. Pharmaceuticals (Basel). 2020 Sep 14;13(9):245

5 Stoffel B et al. POS0365: Anti-TNF glucocorticoid receptor modulator antibody drug conjugate for the treatment of autoimmune diseases. Annals of the Rheumatic Diseases 2021; 80:412-413

6 Buttgereit F et al. OP0115: Efficacy and safety of ABBV-3373, a novel anti-TNF glucocorticoid receptor modulator antibody drug conjugate, in patients with moderate to severe rheumatoid arthritis despite methotrexate therapy: a phase 2a proof of concept study. Annals of the Rheumatic Diseases 2021; 80:64

7 Gillard G et al. OP0307: A novel targeted approach to achieve immune system reset: CD45-targeted antibody drug conjugates ameliorate disease in preclinical autoimmune disease models and enable auto-HSCT. Annals of the Rheumatic Diseases 2020; 79:190-191

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