DuaDeep-SeqAffinity: Dual-Branch Deep Learning for Tri-Stream Sequence-Based Antibody--Antigen Affinity Prediction

Antibody design methods condition on antigen structure to generate complementarity-determining regions (CDR), yet a systematic evaluation of baseline methods reveals that they largely ignore the antigen input. We identify three failure modes that explain this behavior. Antigen blindness arises because models derive predictions from antibody framework context rather than antigen information, producing nearly identical CDRs regardless of the target. Vocabulary collapse reduces predicted amino acids to three to five per position, far below the ground truth distribution in native sequences. Moreover, any model trained with standard per-position cross-entropy converges to the positional marginal distribution, making it provably unable to produce antigen-specific sequence predictions. We propose a novel encoder-decoder architecture called AgForce, that uses a graph neural network (GNN) as the encoder and specialized decoders for sequence-structure co-design. Specifically, we apply framework dropout, gated bottlenecks, and hyperbolic cross attention that prevent the antibody shortcut path. In the decoder, a Mixture Density Network (MDN) sequence head with Potts-like pairwise coupling and annealed Multiple Choice Learning (aMCL) replaces the cross-entropy objective with a multi-component distribution whose optimal solution differs from the positional marginal. An antigen cycle consistency head routes gradients through the sequence decoder, forcing predicted distributions to encode antigen identity. AgForce achieves the best binding quality and sequence recovery simultaneously on the CHIMERA-Bench dataset, improving amino acid recovery by 8% over the strongest sequence baseline while surpassing the baselines across all interface metrics, and nearly doubling the effective vocabulary of GNN methods. The source code is available at: https://github.com/mansoor181/ag-force.git

Accurate ranking of antibody candidates according to their binding affinity is essential for therapeutic antibody discovery. However, existing methods treat affinity comparisons independently and ignore the contextual information encoded in other labeled comparisons, limiting their ability to capture antigen-specific binding landscapes. For many target antigens, a small number of experimentally characterized affinity comparisons are often available. An important question is whether the model can exploit these existing comparisons to infer antigen-specific ranking patterns that facilitate subsequent affinity ranking. This form of learning from labeled demonstrations closely resembles the paradigm of In-Context Learning, motivating us to revisit antibody affinity ranking from an ICL perspective. To this end, we propose AbICL, an ICL framework for antigen-specific antibody affinity ranking. AbICL combines a pretrained structural encoder with a context ranking head and is trained with an episodic meta-training strategy that enables the model to leverage support demonstrations for test-time adaptation without gradient updates. Experiments on the AbRank benchmark demonstrate that AbICL consistently outperforms existing ranking baselines across almost all data splits and evaluation benchmarks. Further analysis shows that the value of contextual demonstrations depends on how well they match the target inference task, and becomes increasingly pronounced under distribution shift and fine-grained affinity discrimination. These findings highlight the potential of ICL as an effective paradigm for antigen-specific antibody affinity ranking, particularly in challenging settings where a single global ranking function is insufficient.

Antibodies are essential proteins that play a central role in immune recognition by binding specific antigen molecules. Although recent protein language models have enabled progress in single-chain protein modeling and generation, they often fall short in antigen-specific antibody design, where effective modeling requires explicit pairing between antibody and antigen, particularly at the epitope level. To address these limitations, we introduce AAMFM, an Antigen-specific Antibody Multimodal Foundation Model that learns unified representations of antibody sequences and structures conditioned on antigen context. AAMFM incorporates rich antigen information including geometric interfaces and epitope annotations via a cross-modal adapter, enabling joint modeling of antibody-antigen interactions in a shared latent space. To further guide the model toward functional relevance, we fine-tune AAMFM using Calibrated Direct Preference Optimization (Cal-DPO), leveraging preference signals extracted from a strong structural prior to align learning with binding-specific objectives. Extensive experiments demonstrate that AAMFM achieves state-of-the-art performance in functional antibody design, revealing its potential for antigen-specific antibody engineering. Our code is available at https://github.com/XL-S224/AAMFM.