Roughly 85% of patients in the TARGET-DERM registry failed to reach the AHEAD taskforce's optimal treatment targets — IGA 0/1, EASI 90 or itch NRS 0/1 — after 12 months on current biologics. That figure anchors a new review published April 15, 2026 in Frontiers in Drug Discovery, in which Yale's Christopher G. Bunick and colleagues survey the bispecific and trispecific antibody pipeline attempting to close the efficacy gap between monospecific biologics and JAK inhibitors in moderate-to-severe atopic dermatitis.

The problem the authors define is mechanistic. Every approved AD biologic — dupilumab (IL-4Rα), tralokinumab and lebrikizumab (IL-13), nemolizumab (IL-31RA) — blocks a single cytokine or receptor. Mechanistic studies show non-responders to IL-4Rα blockade upregulate alternate axes: IL-17, IL-22 and IFN-γ. JAK inhibitors such as upadacitinib and abrocitinib, which suppress Th1, Th2 and Th17/22 signaling simultaneously, reach EASI 90 and itch 0/1 more often. Multi-specific antibodies aim to reproduce that breadth through precise extracellular targeting, ideally with the longer dosing intervals of half-life-engineered molecules.

One construct has already delivered proof-of-concept. In a first-in-patient randomized Phase 1/2a study, UCB's galvokimig (UCB9741) — a trispecific antibody against IL-13, IL-17A and IL-17F with an albumin-binding domain for half-life extension — produced improvements as early as week 2, with approximately 47% of patients (43% placebo-adjusted) achieving EASI 90 at week 12. It is now in Phase 2b.

Pfizer's tilrekimig (PF-07275315), a trispecific targeting IL-4, IL-13 and TSLP, met its primary endpoint in Phase 2: placebo-adjusted EASI 75 rates at week 16 were 38.7%, 51.9% and 49.4% in the low-, middle- and high-dose groups, with a favorable safety profile and Phase 3 expected. Its sister trispecific PF-07264660 (IL-4/IL-13/IL-33) remains in Phase 2.

Keymed's CM512, a TSLP/IL-13 bispecific, posted Phase 1b data in China (n = 46): 300 mg dosing achieved EASI 75 in 50% versus 7% on placebo at week 6, and EASI 90 in 41.7% versus 0% at week 12 — responses sustained through week 24, roughly 20 weeks after the last dose. The molecule showed a half-life of up to 70 days. Apogee's APG279, a cocktail of the half-life-extended anti-IL-13 APG777 (~75-day half-life) and anti-OX40L APG990 (~60-day half-life), entered a Phase 1b head-to-head against dupilumab in 2025.

The itch-focused programs pair IL-4Rα or IL-13 blockade with IL-31 pathway inhibition: BBT001 (Bambusa, Phase 1, ~33-day half-life, single dose suppressed pSTAT6 over 8 weeks), ZL-1503 (Zai Lab, Phase 1b; a single IV dose in nonhuman primates inhibited IL-13-mediated pSTAT6 and scratching for at least 76 days), Attovia's ATTO-3712 and Zymeworks' preclinical ZW1572. A cautionary data point: Numab/J&J's NM26-2198, the IL-4Rα/IL-31 bispecific furthest along, had its Phase 2b terminated as of December 2025 for insufficient efficacy. Triveni Bio's TRIV-509 and TRIV-573 take a different route entirely, inhibiting kallikrein 5/7 proteases, with IL-13 blockade added in the trispecific; ex vivo AD skin showed restored desmoglein-1 expression up to 3-fold.

Half-life engineering separates the field. Most approved biologics run 20–28 days. Fc modification (YTE substitution), albumin binding and tighter FcRn engagement push candidates toward quarterly-or-longer dosing — but only a subset of the pipeline, including APG279, TRIV-509/573, galvokimig and donzakimig, has disclosed such engineering.

The review closes on two uncertainties: whether broader blockade can resolve paradoxical dupilumab-associated head-and-neck dermatitis, which single-cell data link to an IL-22 signature, and whether therapeutic inertia will limit real-world uptake even if superior outcomes emerge. Trial results over the next two years — galvokimig Phase 2b, tilrekimig Phase 3, APG279 versus dupilumab — will determine whether multi-specifics raise the standard of care or expand options only marginally beyond it.