Earlier this year, during the meetings of the American Association for Cancer Research (AACR), held April 16-20 in New Orleans, LA, and the Protein and Antibody Engineering Summit (PEGS) in Boston, MA (April 25 – 29), multiple presentations showed how antibody-drug conjugates (ADCs) have, over the last decade, really revolutionized the field of cancer chemotherapy.
With good reason, ADCs have, essentially, become all the rage for pharmaceutical oncology drug development pipelines.
While the success of the currently approved and marketed ADCs, brentuximab vedotin (Adcetris®; Seattle Genetics) and ado-trastuzumab emtansine (Kadcyla®; Genentech/Roche/Immunogen), has, as one expert explained, been tough to follow, it’s exciting to see that the hard work by dedicated scientists and clinical investigators is indeed bearing fruit!
With >50 ADCs in clinical trials, and an average clinical development time of ~6 – 12 years, the expectation is that in the next 3 – 4 years the number of new, approved, ADCs will increase dramatically.
It’s indeed exciting to see that scientists have met, and are continuing to meet, a number of these and other challenges … in the development of novel antibody-drug conjugates…
Hurdles
The complexity of ADCs present unique development challenges. But what are some of the hurdles to be expected in bringing novel ADCs to the clinic? Following the first generation of ADC chemistries, what are some of the preclinical and clinical lessons and how have these experiences been applied?
New ADCs in clinical development are directed against a range of different targets. However, there are only a limited number of cytotoxic drugs, including calicheamicin, auristatins, maytansinoids, duocarmycins and pyrrolobenzodiazepines (PBDs) confirming the difficulties of finding fitting cytotoxic drugs as payloads in ADCs. How do these highly potent agents support an average of drug-to-antibody ratio (DAR) of 2 to 4? Are they not too hydrophobic? Are they linkable? Are they accessible by simple synthetic pathways? Manufacturable? Is there a relationship between targeted receptor number and the potency of the targeted cytotoxic drug required for therapeutic efficacy?
How can we design a linker in a ligand-targeted drug conjugate that is stable in circulation and cleavable upon endocytosis into tumor cells? What about a case for moderate toxic payloads? What about the sensitivity of cytotoxic agents to multidrug resistance (MDR) mechanisms?
Meeting the challenge
It’s indeed exciting to see that scientists have met, and are continuing to meet, a number of these and other challenges including how to improve the therapeutic index, the selection of the optimal target, a better understanding of mechanism of action (MOA) of existing and new ADCs, how to manage and understand off-target toxicities, as well as the selection of appropriate clinical settings where these novel, targeted, drugs may have the highest clinical benefit. [1]
During the 2016 AACR meeting in April, results from the I-SPY2 TRIAL, in which investigators tested if ado-trastuzumab emtansine + pertuzumab could bring a substantially greater proportion of patients to the primary endpoint of pathological complete response (pCR) compared with paclitaxel + trastuzumab, showed that the combination of ado-trastuzumab emtansine + pertuzumab substantially improved pCR for all subgroups of HER2-positive breast cancers compared with those in the control group. [2]
Investigators expect that this combination will most likely succeed in a confirmatory 300-patient, neoadjuvant, phase III, randomized trial testing ado-trastuzumab emtansine + pertuzumab against paclitaxel + trastuzumab. [2]
PEGS Summit
In late April, during the PEGS Summit in Boston, attendees discussed the complexity of antibody-drug conjugates with its many moving parts. The confirmed consensus is that these ‘moving parts’ make the field of antibody-drug conjugates incredibly challenging, and yet, it offers scientists a full spectrum and potential for innovation. From new targeting ligands to new conjugation methods, from multiple payloads to changing the drug-antibody ratio (DAR), all these are challenging the convention for the design and development of next-generation ADCs.
Progress in site-specific conjugation modalities, optimization of linkers with balanced stability and identification of novel, potent cytotoxic agents are expected to pave the way for a better understanding of factors such as ADC efficacy, PK and safety. A robust clinical pipeline, evolving clinical data, technological advancements and a better understanding of the biology of cancer and hematological malignancies, is expected to aid the development of these novel ADCs.
ASCO 2016
This year, the theme of the annual meeting of the American Society of Clinical Oncology (ASCO) to be held June 3 – 7 in Chicago, Ill. is Collective Wisdom: The Future of Patient-Centered Care and Research, emphasizing that the combined knowledge from various disciplines, cancer types, treatment approaches, and big data technologies is essential to progress. [3]
The 2016 theme is expected to reinforces the inextricable link – a necessity – between ongoing clinical research and advances in patient-centered care. This theme is expected to be evident when the latest, most exciting discoveries, based on a better understanding of cancer biology and chemistry – crucial in the development of novel ADCs – will be presented.
As the executive editor of ADC Review / Journal of Antibody-drug Conjugates (published by InPress Media Group), I’m looking forward to see the updated results from a large number of (ongoing) clinical trials during ASCO this year. In addition to updates for brentuximab vedotin and ado-trastuzumab emtansine, oral and poster presentations during ASCO will include the latest – often late breaking abstracts – for [3]:
- Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate (IMMU-132), being developed by Immunomedics;
- Rovalpituzumab tesirine (Rova-T/SC16LD6.5; Stemcentrx/AbbVie), a delta-like protein 3 (DLL3)-targeted antibody-drug conjugate for the treatment of recurrent or refractory small cell lung cancer (SCLC);
- An anti-PSMA ADC (Ambrx) being developed for the treatment of patients with prostate cancer and glioblastoma multiforme;
- Enfortumab vedotin (Agensys), a human anti-nectin-4 antibody conjugated to monomethyl auristatin E (MMAE) for the treatment of multiple solid tumors;
- Inotuzumab ozogamicin (Pfizer) for the treatment of patients with relapsed/refractory acute lymphoblastic leukemia;
- Anetumab ravtansine (BAY 94-9343) an anti-mesothelin antibody drug conjugate for the potential treatment of mesotheliomas as well as ovarian and pancreatic cancers;
- ABBV-399 (AbbVie), an antibody drug conjugate targeting c-Met, in patients with advanced solid tumors;
- Mirvetuximab soravtansine (IMGN853; Immunogen), a folate receptor alpha (FRα)-targeting antibody-drug conjugate in clinical trials as single agent activity in platinum-resistant epithelial ovarian cancer;
- Lifastuzumab vedotin, also known as DNIB0600A and RG-7599 is being developed by Genentech/Roche. In clinical trials lifastuzumab vedotin is compared to pegylated liposomal doxorubicin for the treatment of patients with platinum-resistant ovarian cancer.
In addition to these ADCs, results are expected for SAR566658, ABT-414 and other ADCs.
This year, the annual meeting of the American Society of Clinical Oncology is expected to draw approximately 30,000+ scientists, clinicians, (patient) advocates, and others who will listen, learn and discuss advances in the treatment of cancer.
Our editorial team will be present in Chicago to bring you exciting news and (late) breaking (clinical) updates as well as interviews with the dedicated scientists, physicians and other professionals involved in ongoing research.
Expect to see reports and stirring news from ongoing clinical trials with novel antibody-drug conjugates, confirming the exciting advances and meaningful benefits for patients – now and in the future.
Click here to see an overview of oral and poster presentations of antibody-drug conjugates to be presented at ASCO this year. For additional information to plan your meeting attendance, visit ASCO’s iPlanner page.
