The journey of ABBV-085 began back in 2018 when AbbVie Biotherapeutics and Cleveland Clinic researchers identified leucine-rich repeat containing 15 or LRRC15 as a novel marker on mesenchymal origin cancerous cells and cancer-associated fibroblasts. It is found highly expressed in the tumour microenvironment and many of the solid tumour types and is fundamentally a type 1 transmembrane protein. Samrotamab vedotin or ABBV-085 is an ADC being developed by AbbVie. ABBV-085 or synonymously known as ADC ABBV-085, PR-1498487 PAB-MMAE, Samrotamab Vedotin or SAMROTAMAB VEDOTIN is a monoclonal antibody that is bioconjugated to the cytotoxic payload monomethyl auristatin E. It specifically targets leucine-rich repeat containing 15 (LRRC15) which is abundantly found on cancerous cells and almost absent or scarcely present on normal tissue cell surfaces. It is formulated in a PBS buffer at 7.5 pH and administered intravenously. When it's introduced in the body, the mAb or monoclonal antibody moiety of ABBV-085 specifically binds to the abundantly found LRRC15 of tumour cells. After internalisation, the cytotoxic payload/ drug is released and kills the cancerous cells; the cytotoxic mechanism of action of the drug is not yet clear.
A similar antibody drug conjugate - Polatuzumab vedotin
The trail
The 2018 findings supported the development of LRRC15-targeted antibody drug conjugate ABBV-085 and also provided preclinical evidence of antineoplastic efficacy, showing the way to clinical trials. In 2019, the phase I trial in Solid tumours in patients with late-stage disease conditions and inoperable or unresectable tumors, results consisted of efficacy, pharmacokinetic and adverse events data and was presented at the 55th American Society of Clinical Oncology's Annual Meeting.
What does the recent clinical trial study say?
George D. Demetri et al recently published "First-in-Human Phase I Study of ABBV-085, an Antibody–Drug Conjugate Targeting LRRC15, in Sarcomas and Other Advanced Solid Tumors", clinical trials: targeted therapy in Clinical Cancer Research 2021, American Association for Cancer Research; 27:3556–66. ABBV-085 crossed the First-in-Human Phase I Clinical Trial (NCT02565758) wherein its pharmacokinetics/pharmacodynamics, safety and preliminary antitumor activity were assessed. Dose expansion and dose escalation were the two major parts of the study. The intravenous infusion was administered as 0.3 to 6.0 mg/kg every 14 days. Out of 85 enrolled patients, 45 were given 3.6 mg/kg per 2 weeks, monotherapy of ABBV-085 as the expansion dose. This included 10 with osteosarcoma and 10 with UPS. Decreased appetite, nausea, fatigue - were the commonest adverse effects associated with the ABBV-085 therapy. The overall response rate for patients with UPS/ osteosarcoma treated at 3.6 mg/kg was a promising 20% with 4 confirmed partial responses. The median duration of objective response was 8 mos in patients with a confirmed PR. The results ultimately showed the ADC formulation to be tolerable and safe at a dose of 3.6 mg/kg every 2 weeks.
Figure 2.
A sneak-peek into the trial data.
In figure 2A - “all sarcomas at all doses” population the objective response rate was 10.8%. The ORR or objective response rate was 20% in the patients with UPS or osteosarcoma and they were treated at the 3.6 mg/kg dose. Figure 2B and C show 4 patients, among the UPS patients, who showed a partial response PR with more than 30% tumor shrinkage and 2 confirmed PR out of 4. The median duration of objective response, for the 4 sarcoma patients with a confirmed partial response was 7.8 mos, with a median reduction in tumor diameter from 60.6%. In figure 2B and D, 2 osteosarcoma patients had a confirmed partial response. Only a single partial response was observed in the “non sarcoma at all doses” population. This patient with colon/rectal cancer had a duration of objective response of 5.7 mos with a 50% reduction in tumor diameter. The patient received ABBV-085 and gemcitabine as the cytotoxic payload. No response was shown by 18 non sarcoma patients treated with ABBV-085 monotherapy at the same dose.
Conclusively, ABBV-085 dosing showed a preliminary antitumor activity and an acceptable safety profile in osteosarcoma and UPS patients with LRRC15 expression in tumour stroma/ microenvironment as well as on cancerous-cell surface. The researchers believe that targeting LRRC15 investigation in these patients may be further pursued due to high unmet patient group requirement.
References:
1. Primary reference: G. Demetri et al, Clin Cancer Res 2021;27:3556–66 DOI: 10.1158/1078-0432.CCR-20-4513 Published July 2021.
Content by Sakshi Kasat
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